SMAD6 (SMAD family member 6)

Gene

• Entrez ID: 4091
• Gene name: SMAD family member 6
• Gene symbol: SMAD6
• Synonyms (NCBI Gene): AOVD2, HsT17432, MADH6, MADH7
• Chromosome: 15
• Chromosome location: 15q22.31
• Summary: The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila `mothers against decapentaplegic` (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs387907283	G>A,T	Uncertain-significance, pathogenic	Coding sequence variant, genic downstream transcript variant, non coding transcript variant, missense variant
rs387907284	C>G,T	Pathogenic	Coding sequence variant, genic downstream transcript variant, non coding transcript variant, missense variant
rs761888345	C>T	Risk-factor	Missense variant, genic downstream transcript variant, non coding transcript variant, coding sequence variant
rs768542939	G>A,C	Pathogenic	Missense variant, upstream transcript variant, non coding transcript variant, genic upstream transcript variant, coding sequence variant
rs900988907	C>A,G	Pathogenic	Genic downstream transcript variant, coding sequence variant, non coding transcript variant, missense variant
rs958818801	CGGGCGG>-,CGGGCGGCGGGCGG	Likely-pathogenic, uncertain-significance	Genic upstream transcript variant, upstream transcript variant, non coding transcript variant, frameshift variant, coding sequence variant
rs1057517824	T>A	Likely-pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, missense variant
rs1064793003	C>T	Risk-factor	Stop gained, genic upstream transcript variant, upstream transcript variant, non coding transcript variant, coding sequence variant
rs1085307122	G>-	Risk-factor	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, frameshift variant
rs1160042861	C>A,T	Pathogenic	Stop gained, genic upstream transcript variant, missense variant, upstream transcript variant, non coding transcript variant, coding sequence variant
rs1231501584	G>A	Pathogenic	Genic upstream transcript variant, upstream transcript variant, stop gained, coding sequence variant, non coding transcript variant
rs1246889300	G>A,C,T	Likely-pathogenic, pathogenic, uncertain-significance	Genic upstream transcript variant, upstream transcript variant, missense variant, stop gained, coding sequence variant, non coding transcript variant
rs1395007983	C>A,G,T	Pathogenic	Genic upstream transcript variant, non coding transcript variant, upstream transcript variant, coding sequence variant, missense variant
rs1419095990	G>A,C	Pathogenic	Non coding transcript variant, genic upstream transcript variant, upstream transcript variant, coding sequence variant, missense variant
rs1447391811	C>A,T	Likely-pathogenic	Synonymous variant, upstream transcript variant, genic upstream transcript variant, stop gained, non coding transcript variant, coding sequence variant
rs1567092020	C>T	Pathogenic	Non coding transcript variant, genic upstream transcript variant, missense variant, coding sequence variant, upstream transcript variant
rs1567092071	A>-	Pathogenic	Non coding transcript variant, genic upstream transcript variant, coding sequence variant, frameshift variant, upstream transcript variant
rs1595756416	->G	Pathogenic	Non coding transcript variant, genic upstream transcript variant, coding sequence variant, frameshift variant, upstream transcript variant
rs1595756640	C>T	Pathogenic	Non coding transcript variant, genic upstream transcript variant, stop gained, coding sequence variant, upstream transcript variant
rs1595756703	GC>T	Likely-pathogenic	Non coding transcript variant, genic upstream transcript variant, coding sequence variant, frameshift variant, upstream transcript variant
rs1595756962	G>A	Likely-pathogenic	Non coding transcript variant, genic upstream transcript variant, missense variant, coding sequence variant, upstream transcript variant
rs1595757203	T>-	Pathogenic	Non coding transcript variant, genic upstream transcript variant, coding sequence variant, frameshift variant, upstream transcript variant
rs1595757398	G>A	Likely-pathogenic	Non coding transcript variant, genic upstream transcript variant, stop gained, coding sequence variant, upstream transcript variant
rs1595766210	G>T	Pathogenic	Non coding transcript variant, downstream transcript variant, stop gained, coding sequence variant, genic downstream transcript variant
rs1595804976	->GGCATC	Pathogenic	Non coding transcript variant, coding sequence variant, genic downstream transcript variant, inframe insertion

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT001951	hsa-miR-520h	Luciferase reporter assay	18189265
MIRT001951	hsa-miR-520h	Microarray;Other	18189265
MIRT030225	hsa-miR-26b-5p	Microarray	19088304
MIRT627567	hsa-miR-8066	HITS-CLIP	23824327
MIRT627566	hsa-miR-4501	HITS-CLIP	23824327
MIRT627565	hsa-miR-6832-3p	HITS-CLIP	23824327
MIRT627564	hsa-miR-4287	HITS-CLIP	23824327
MIRT627563	hsa-miR-4685-3p	HITS-CLIP	23824327
MIRT627562	hsa-miR-3124-3p	HITS-CLIP	23824327
MIRT627561	hsa-miR-134-5p	HITS-CLIP	23824327
MIRT627560	hsa-miR-3118	HITS-CLIP	23824327
MIRT627559	hsa-miR-3164	HITS-CLIP	23824327
MIRT627558	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT627557	hsa-miR-204-5p	HITS-CLIP	23824327
MIRT627556	hsa-miR-211-5p	HITS-CLIP	23824327
MIRT627555	hsa-miR-4691-5p	HITS-CLIP	23824327
MIRT627554	hsa-miR-6792-3p	HITS-CLIP	23824327
MIRT627553	hsa-miR-6749-3p	HITS-CLIP	23824327
MIRT627552	hsa-miR-670-3p	HITS-CLIP	23824327
MIRT627551	hsa-miR-1238-3p	HITS-CLIP	23824327
MIRT627550	hsa-miR-1305	HITS-CLIP	23824327
MIRT627567	hsa-miR-8066	HITS-CLIP	23824327
MIRT627566	hsa-miR-4501	HITS-CLIP	23824327
MIRT627565	hsa-miR-6832-3p	HITS-CLIP	23824327
MIRT627564	hsa-miR-4287	HITS-CLIP	23824327
MIRT627563	hsa-miR-4685-3p	HITS-CLIP	23824327
MIRT627562	hsa-miR-3124-3p	HITS-CLIP	23824327
MIRT627561	hsa-miR-134-5p	HITS-CLIP	23824327
MIRT627560	hsa-miR-3118	HITS-CLIP	23824327
MIRT627559	hsa-miR-3164	HITS-CLIP	23824327
MIRT627558	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT627557	hsa-miR-204-5p	HITS-CLIP	23824327
MIRT627556	hsa-miR-211-5p	HITS-CLIP	23824327
MIRT627555	hsa-miR-4691-5p	HITS-CLIP	23824327
MIRT627554	hsa-miR-6792-3p	HITS-CLIP	23824327
MIRT627553	hsa-miR-6749-3p	HITS-CLIP	23824327
MIRT627552	hsa-miR-670-3p	HITS-CLIP	23824327
MIRT627551	hsa-miR-1238-3p	HITS-CLIP	23824327
MIRT627550	hsa-miR-1305	HITS-CLIP	23824327
MIRT140800	hsa-miR-106b-5p	HITS-CLIP	22473208
MIRT140794	hsa-miR-20a-5p	HITS-CLIP	22473208
MIRT439143	hsa-let-7c-5p	3'LIFE	25074381
MIRT140800	hsa-miR-106b-5p	HITS-CLIP	22473208
MIRT140790	hsa-miR-17-5p	HITS-CLIP	22473208
MIRT140803	hsa-miR-20b-5p	HITS-CLIP	22473208
MIRT140798	hsa-miR-93-5p	HITS-CLIP	22473208
MIRT140805	hsa-miR-519d-3p	HITS-CLIP	22473208
MIRT140794	hsa-miR-20a-5p	HITS-CLIP	22473208
MIRT140797	hsa-miR-92a-3p	HITS-CLIP	22473208
MIRT140807	hsa-miR-92b-3p	HITS-CLIP	22473208
MIRT140796	hsa-miR-32-5p	HITS-CLIP	22473208
MIRT439143	hsa-let-7c-5p	3'LIFE	25074381
MIRT627567	hsa-miR-8066	HITS-CLIP	23824327
MIRT627566	hsa-miR-4501	HITS-CLIP	23824327
MIRT627565	hsa-miR-6832-3p	HITS-CLIP	23824327
MIRT627564	hsa-miR-4287	HITS-CLIP	23824327
MIRT627563	hsa-miR-4685-3p	HITS-CLIP	23824327
MIRT627562	hsa-miR-3124-3p	HITS-CLIP	23824327
MIRT627561	hsa-miR-134-5p	HITS-CLIP	23824327
MIRT627560	hsa-miR-3118	HITS-CLIP	23824327
MIRT627559	hsa-miR-3164	HITS-CLIP	23824327
MIRT627558	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT627557	hsa-miR-204-5p	HITS-CLIP	23824327
MIRT627556	hsa-miR-211-5p	HITS-CLIP	23824327
MIRT627555	hsa-miR-4691-5p	HITS-CLIP	23824327
MIRT627554	hsa-miR-6792-3p	HITS-CLIP	23824327
MIRT627553	hsa-miR-6749-3p	HITS-CLIP	23824327
MIRT627552	hsa-miR-670-3p	HITS-CLIP	23824327
MIRT627551	hsa-miR-1238-3p	HITS-CLIP	23824327
MIRT627550	hsa-miR-1305	HITS-CLIP	23824327
MIRT627567	hsa-miR-8066	HITS-CLIP	23824327
MIRT627566	hsa-miR-4501	HITS-CLIP	23824327
MIRT627565	hsa-miR-6832-3p	HITS-CLIP	23824327
MIRT627564	hsa-miR-4287	HITS-CLIP	23824327
MIRT627563	hsa-miR-4685-3p	HITS-CLIP	23824327
MIRT627562	hsa-miR-3124-3p	HITS-CLIP	23824327
MIRT627561	hsa-miR-134-5p	HITS-CLIP	23824327
MIRT627560	hsa-miR-3118	HITS-CLIP	23824327
MIRT627559	hsa-miR-3164	HITS-CLIP	23824327
MIRT627558	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT627557	hsa-miR-204-5p	HITS-CLIP	23824327
MIRT627556	hsa-miR-211-5p	HITS-CLIP	23824327
MIRT627555	hsa-miR-4691-5p	HITS-CLIP	23824327
MIRT627554	hsa-miR-6792-3p	HITS-CLIP	23824327
MIRT627553	hsa-miR-6749-3p	HITS-CLIP	23824327
MIRT627552	hsa-miR-670-3p	HITS-CLIP	23824327
MIRT627551	hsa-miR-1238-3p	HITS-CLIP	23824327
MIRT627550	hsa-miR-1305	HITS-CLIP	23824327
MIRT1371025	hsa-miR-1224-3p	CLIP-seq
MIRT1371026	hsa-miR-1260	CLIP-seq
MIRT1371027	hsa-miR-1260b	CLIP-seq
MIRT1371028	hsa-miR-1280	CLIP-seq
MIRT1371029	hsa-miR-2052	CLIP-seq
MIRT1371030	hsa-miR-2355-3p	CLIP-seq
MIRT1371031	hsa-miR-25	CLIP-seq
MIRT1371032	hsa-miR-3119	CLIP-seq
MIRT1371033	hsa-miR-3194-3p	CLIP-seq
MIRT1371034	hsa-miR-32	CLIP-seq
MIRT1371035	hsa-miR-329	CLIP-seq
MIRT1371036	hsa-miR-362-3p	CLIP-seq
MIRT1371037	hsa-miR-363	CLIP-seq
MIRT1371038	hsa-miR-3648	CLIP-seq
MIRT1371039	hsa-miR-367	CLIP-seq
MIRT1371040	hsa-miR-3692	CLIP-seq
MIRT1371041	hsa-miR-3941	CLIP-seq
MIRT1371042	hsa-miR-410	CLIP-seq
MIRT1371043	hsa-miR-4646-3p	CLIP-seq
MIRT1371044	hsa-miR-4718	CLIP-seq
MIRT1371045	hsa-miR-4789-5p	CLIP-seq
MIRT1371046	hsa-miR-532-3p	CLIP-seq
MIRT1371047	hsa-miR-578	CLIP-seq
MIRT1371048	hsa-miR-603	CLIP-seq
MIRT1371049	hsa-miR-767-5p	CLIP-seq
MIRT1371050	hsa-miR-92a	CLIP-seq
MIRT1371051	hsa-miR-92b	CLIP-seq
MIRT1371052	hsa-miR-134	CLIP-seq
MIRT1371053	hsa-miR-196a	CLIP-seq
MIRT1371054	hsa-miR-196b	CLIP-seq
MIRT1371055	hsa-miR-3125	CLIP-seq
MIRT1371056	hsa-miR-3126-3p	CLIP-seq
MIRT1371057	hsa-miR-3163	CLIP-seq
MIRT1371058	hsa-miR-3682-3p	CLIP-seq
MIRT1371059	hsa-miR-369-3p	CLIP-seq
MIRT1371060	hsa-miR-374a	CLIP-seq
MIRT1371061	hsa-miR-374b	CLIP-seq
MIRT1371062	hsa-miR-3916	CLIP-seq
MIRT1371063	hsa-miR-3927	CLIP-seq
MIRT1371042	hsa-miR-410	CLIP-seq
MIRT1371064	hsa-miR-4476	CLIP-seq
MIRT1371065	hsa-miR-4533	CLIP-seq
MIRT1371066	hsa-miR-4667-5p	CLIP-seq
MIRT1371067	hsa-miR-4700-5p	CLIP-seq
MIRT1371068	hsa-miR-4736	CLIP-seq
MIRT1371069	hsa-miR-4749-3p	CLIP-seq
MIRT1371070	hsa-miR-4795-3p	CLIP-seq
MIRT1371071	hsa-miR-516a-5p	CLIP-seq
MIRT1371072	hsa-miR-548a-3p	CLIP-seq
MIRT1371073	hsa-miR-548a-5p	CLIP-seq
MIRT1371074	hsa-miR-548ab	CLIP-seq
MIRT1371075	hsa-miR-548ak	CLIP-seq
MIRT1371076	hsa-miR-548b-5p	CLIP-seq
MIRT1371077	hsa-miR-548c-5p	CLIP-seq
MIRT1371078	hsa-miR-548d-5p	CLIP-seq
MIRT1371079	hsa-miR-548e	CLIP-seq
MIRT1371080	hsa-miR-548f	CLIP-seq
MIRT1371081	hsa-miR-548h	CLIP-seq
MIRT1371082	hsa-miR-548i	CLIP-seq
MIRT1371083	hsa-miR-548j	CLIP-seq
MIRT1371084	hsa-miR-548n	CLIP-seq
MIRT1371085	hsa-miR-548w	CLIP-seq
MIRT1371086	hsa-miR-548y	CLIP-seq
MIRT1371087	hsa-miR-559	CLIP-seq
MIRT1371088	hsa-miR-587	CLIP-seq
MIRT1371089	hsa-miR-637	CLIP-seq
MIRT1371090	hsa-miR-656	CLIP-seq
MIRT2110144	hsa-miR-4258	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
CREB1	Activation	14755548

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000785	Component	Chromatin	ISA
GO:0000976	Function	Transcription cis-regulatory region binding	IDA	16491121
GO:0001657	Process	Ureteric bud development	IEA
GO:0003148	Process	Outflow tract septum morphogenesis	IEA
GO:0003148	Process	Outflow tract septum morphogenesis	ISS
GO:0003170	Process	Heart valve development	IEA
GO:0003180	Process	Aortic valve morphogenesis	IMP	22275001
GO:0003183	Process	Mitral valve morphogenesis	IEA
GO:0003183	Process	Mitral valve morphogenesis	ISS
GO:0003184	Process	Pulmonary valve morphogenesis	IEA
GO:0003184	Process	Pulmonary valve morphogenesis	ISS
GO:0003281	Process	Ventricular septum development	IEA
GO:0003682	Function	Chromatin binding	IDA	16491121
GO:0005515	Function	Protein binding	IPI	9436979, 11483516, 16299379, 16491121, 21791611
GO:0005634	Component	Nucleus	IDA	16491121
GO:0005634	Component	Nucleus	IEA
GO:0005654	Component	Nucleoplasm	IDA
GO:0005667	Component	Transcription regulator complex	IEA
GO:0005737	Component	Cytoplasm	IDA	33667543
GO:0005737	Component	Cytoplasm	TAS	19018011
GO:0005794	Component	Golgi apparatus	IDA
GO:0005829	Component	Cytosol	IDA
GO:0005829	Component	Cytosol	TAS
GO:0005929	Component	Cilium	IDA
GO:0006355	Process	Regulation of DNA-templated transcription	IEA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA
GO:0006955	Process	Immune response	IMP	16886151
GO:0007352	Process	Zygotic specification of dorsal/ventral axis	IMP	9436979
GO:0008285	Process	Negative regulation of cell population proliferation	IMP	19047146
GO:0009653	Process	Anatomical structure morphogenesis	IBA
GO:0016604	Component	Nuclear body	IDA
GO:0030154	Process	Cell differentiation	IBA
GO:0030279	Process	Negative regulation of ossification	IEA
GO:0030279	Process	Negative regulation of ossification	ISS
GO:0030509	Process	BMP signaling pathway	IBA
GO:0030509	Process	BMP signaling pathway	IDA	8653785, 9389648
GO:0030509	Process	BMP signaling pathway	IDA	23455153
GO:0030512	Process	Negative regulation of transforming growth factor beta receptor signaling pathway	IDA	9256479
GO:0030512	Process	Negative regulation of transforming growth factor beta receptor signaling pathway	IEA
GO:0030512	Process	Negative regulation of transforming growth factor beta receptor signaling pathway	IMP	19047146
GO:0030514	Process	Negative regulation of BMP signaling pathway	IDA	9436979, 33667543
GO:0030514	Process	Negative regulation of BMP signaling pathway	IEA
GO:0030514	Process	Negative regulation of BMP signaling pathway	IMP	22275001, 30848080
GO:0031589	Process	Cell-substrate adhesion	IMP	16491121
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	11278251
GO:0032496	Process	Response to lipopolysaccharide	IDA	19193853
GO:0032926	Process	Negative regulation of activin receptor signaling pathway	IDA	16720724
GO:0032926	Process	Negative regulation of activin receptor signaling pathway	IEA
GO:0032991	Component	Protein-containing complex	IDA	23610558
GO:0034616	Process	Response to laminar fluid shear stress	IEA
GO:0034616	Process	Response to laminar fluid shear stress	IEP	9256479
GO:0034713	Function	Type I transforming growth factor beta receptor binding	IDA	9436979
GO:0034713	Function	Type I transforming growth factor beta receptor binding	IEA
GO:0035904	Process	Aorta development	IEA
GO:0036064	Component	Ciliary basal body	IDA
GO:0036064	Component	Ciliary basal body	IEA
GO:0042802	Function	Identical protein binding	IPI	9436979
GO:0043066	Process	Negative regulation of apoptotic process	IMP	19047146
GO:0043627	Process	Response to estrogen	IEA
GO:0045444	Process	Fat cell differentiation	IDA	23455153
GO:0045596	Process	Negative regulation of cell differentiation	IEA
GO:0045668	Process	Negative regulation of osteoblast differentiation	IMP	22275001
GO:0046872	Function	Metal ion binding	IEA
GO:0060392	Process	Negative regulation of SMAD protein signal transduction	IDA	9436979
GO:0060392	Process	Negative regulation of SMAD protein signal transduction	IEA
GO:0060392	Process	Negative regulation of SMAD protein signal transduction	IMP	19047146
GO:0060395	Process	SMAD protein signal transduction	IBA
GO:0060976	Process	Coronary vasculature development	IEA
GO:0070410	Function	Co-SMAD binding	IPI	9256479
GO:0070411	Function	I-SMAD binding	IBA
GO:0070411	Function	I-SMAD binding	IEA
GO:0070411	Function	I-SMAD binding	IPI	9256479
GO:0070412	Function	R-SMAD binding	IPI	9256479, 9436979
GO:0070697	Function	Activin receptor binding	IEA
GO:0070698	Function	Type I activin receptor binding	IDA	9436979
GO:0071144	Component	Heteromeric SMAD protein complex	IBA
GO:0071363	Process	Cellular response to growth factor stimulus	IEA
GO:0140311	Function	Protein sequestering activity	IDA	33667543
GO:0140416	Function	Transcription regulator inhibitor activity	IBA
GO:0140416	Function	Transcription regulator inhibitor activity	IDA	9256479
GO:0140416	Function	Transcription regulator inhibitor activity	IEA
GO:0140416	Function	Transcription regulator inhibitor activity	TAS	19018011
GO:0141091	Process	Transforming growth factor beta receptor superfamily signaling pathway	IEA
GO:1902895	Process	Positive regulation of miRNA transcription	IEA

Other IDs

• MIM: 602931
• HGNC: 6772
• e!Ensembl: ENSG00000137834

Protein

• UniProt ID: O43541
• Protein name: Mothers against decapentaplegic homolog 6 (MAD homolog 6) (Mothers against DPP homolog 6) (SMAD family member 6) (SMAD 6) (Smad6) (hSMAD6)
• Protein function: Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-b
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF03165	MH1	172 → 270	MH1 domain	Domain
  PF03166	MH2	329 → 493	MH2 domain	Family

• Tissue specificity: TISSUE SPECIFICITY: [Isoform B]: Expressed in the brain, heart, ovary, peripheral blood leukocytes, small intestine, spleen, thymus, bone marrow, fetal liver and lymph nodes. {ECO:0000269|PubMed:11284962}.
• Sequence:

  MFRSKRSGLVRRLWRSRVVPDREEGGSGGGGGGDEDGSLGSRAEPAPRAREGGGCGRSEV
  RPVAPRRPRDAVGQRGAQGAGRRRRAGGPPRPMSEPGAGAGSSLLDVAEPGGPGWLPESD
  CETVTCCLFSERDAAGAPRDASDPLAGAALEPAGGGRSREARSRLLLLEQELKTVTYSLL
  KRLKERSLDTLLEAVESRGGVPGGCVLVPRADLRLGGQPAPPQLLLGRLFRWPDLQHAVE
  LKPLCGCHSFAAAADGPTVCCNPYHFSRLCGPESPPPPYSRLSPRDEYKPLDLSDSTLSY
  TETEATNSLITAPGEFSDASMSPDATKPSHWCSVAYWEHRTRVGRLYAVYDQAVSIFYDL
  PQGSGFCLGQLNLEQRSESVRRTRSKIGFGILLSKEPDGVWAYNRGEHPIFVNSPTLDAP
  GGRALVVRKVPPGYSIKVFDFERSGLQHAPEPDAADGPYDPNSVRISFAKGWGPCYSRQF
  ITSCPCWLEILLNNPR

• Sequence length: 496

Pathways

KEGG:

TGF-beta signaling pathway

Reactome:

Signaling by BMP
RUNX2 regulates bone development

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Abnormal axial skeleton morphology	Pathogenic; Likely pathogenic	rs755868380, rs2140581013	RCV001799808 RCV001799787	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Aortic valve disease 1	Pathogenic; Likely pathogenic	rs1567092020, rs900988907	RCV000770958 RCV000770957	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Aortic valve disease 2	Likely pathogenic; Pathogenic	rs2140581013, rs1424182433, rs2140596481, rs2541900116, rs1567092048, rs1325349483, rs387907283, rs1595804976	RCV005005252 RCV005051916 RCV001783779 RCV003985972 RCV004555162 RCV004555360 RCV000030753 RCV000787047	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Craniosynostosis 7	Likely pathogenic; Pathogenic	rs2140581013, rs868327024, rs1893041298	RCV005005252 RCV003151401 RCV001283760	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Frontal bossing	Pathogenic	rs1894566397	RCV001799801	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Heart, malformation of	Pathogenic	rs2140681185, rs1894566397	RCV001799771 RCV001799801	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Plagiocephaly	Pathogenic	rs2140581198	RCV001799791	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Polydactyly	Pathogenic	rs2140681839	RCV001799798	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Premature closure of fontanelles	Pathogenic	rs1894566397	RCV001799801	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Radioulnar synostosis	Pathogenic; Likely pathogenic	rs2140580300, rs2140580364, rs1893016936, rs1893018000, rs2140580751, rs755868380, rs1893025235, rs1893025784, rs2140581013, rs2140581167, rs2140581198, rs2140581279, rs2140581633, rs1893037722, rs1893041246, rs570279865, rs2140596499, rs2140680984, rs753110746, rs2140681185, rs2140681497, rs751622656, rs2140681839, rs1894566397, rs1255802415, rs746469222, rs1894573824, rs1432193098, rs1595756416, rs1595756703, rs1231501584, rs1595756962, rs1595757203, rs1595763070, rs1595766210	RCV001799769 RCV001799785 RCV001799772 RCV001799793 RCV001799779 RCV001799808 RCV001799806 RCV001799780 RCV001799787 RCV001799790 RCV001799791 RCV001799792 RCV001799775 RCV001799796 RCV001799777 RCV001799774 RCV001799773 RCV001799767 RCV001799802 RCV001799771 RCV001799807 RCV001799803 RCV001799798 RCV001799801 RCV001799799 RCV001799784 RCV001799800 RCV001799778 RCV000851358 RCV000851351 RCV000851355 RCV000851361 RCV000851360 RCV000851357 RCV000851356	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Radioulnar synostosis, nonsyndromic, susceptibility to	Likely pathogenic	rs2140581013, rs2140681546	RCV005005252 RCV004820885	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
SMAD6-related disorder	Likely pathogenic	rs2545311830	RCV003406162	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Thoracic aortic aneurysm	Likely pathogenic	rs1411192932	RCV001751796	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Aneurysm-osteoarthritis syndrome	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ATRIAL FIBRILLATION	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ATYPICAL FEMORAL FRACTURE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BENIGN NEOPLASM	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Bicuspid aortic valve	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
BICUSPID AORTIC VALVE DISEASE	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CARPAL TUNNEL SYNDROME	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
COLORECTAL ADENOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
COLORECTAL CANCER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL HEART DEFECTS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL HEART DEFECTS, MULTIPLE TYPE S	—	GenCC	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL RADIOULNAR SYNOSTOSIS	—	GenCC	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CRANIOSYNOSTOSES	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CRANIOSYNOSTOSIS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CRANIOSYNOSTOSIS 7, SUSCEPTIBILITY TO	risk factor; Conflicting classifications of pathogenicity; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Craniosynostosis syndrome	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Esophageal atresia/tracheoesophageal fistula	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
FAMILIAL BICUSPID AORTIC VALVE	—	Disgenet, GWAS catalog Disgenet, GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Joubert syndrome 9	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
LOEYS-DIETZ SYNDROME 3	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
LUNG CARCINOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OPEN-ANGLE GLAUCOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OSTEOARTHRITIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OSTEOARTHRITIS, HIP	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TETRALOGY OF FALLOT	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYPE 2 DIABETES MELLITUS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acrocephaly	Acrocephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Adenocarcinoma of large intestine	Colorectal Cancer	GWASCAT_DG	30510241, 31089142		★☆☆☆☆ Found in Text Mining only
Adenocarcinoma of lung (disorder)	Lung adenocarcinoma	BEFREE	31503425		★☆☆☆☆ Found in Text Mining only
Adenoma of large intestine	Colorectal adenoma	GWASCAT_DG	30510241		★☆☆☆☆ Found in Text Mining only
Aneurysm of aortic arch	Aneurysm Of Aortic Arch	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aortic Aneurysm	Aortic Aneurysm	BEFREE	30796334		★☆☆☆☆ Found in Text Mining only
Aortic Aneurysm	Aortic Aneurysm	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aortic Aneurysm Thoracic	Thoracic aortic aneurysm	Pubtator	30796334	Associate	★☆☆☆☆ Found in Text Mining only
Aortic coarctation	Aortic Coarctation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aortic valve calcification	Aortic valve calcification	ORPHANET_DG	22275001		★☆☆☆☆ Found in Text Mining only
Aortic valve calcification	Aortic valve calcification	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aortic Valve Disease 1	Aortic valve calcification	ORPHANET_DG	22275001		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Aortic Valve Disease 1	Aortic valve calcification	CLINVAR_DG			★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
AORTIC VALVE DISEASE 2	Aortic Valve Disease	UNIPROT_DG	22275001		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
AORTIC VALVE DISEASE 2	Aortic Valve Disease	GENOMICS_ENGLAND_DG	22275001, 30963242		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
AORTIC VALVE DISEASE 2	Aortic Valve Disease	CLINVAR_DG			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
AORTIC VALVE DISEASE 2	Aortic Valve Disease	CTD_human_DG			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Aortic valve disorder	Aortic Valve Disease	ORPHANET_DG	22275001		★☆☆☆☆ Found in Text Mining only
Aortic Valve Insufficiency	Aortic Valve Insufficiency	HPO_DG			★☆☆☆☆ Found in Text Mining only
Aortic Valve Stenosis	Aortic Valve Sclerosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Arteriovenous Malformations	Arteriovenous malformations	Pubtator	36198763	Inhibit	★☆☆☆☆ Found in Text Mining only
Autism Spectrum Disorder	Autism	Pubtator	34948243	Associate	★☆☆☆☆ Found in Text Mining only
Autistic Disorder	Autism	Pubtator	34208845	Associate	★☆☆☆☆ Found in Text Mining only
Bicuspid aortic valve	Bicuspid aortic valve	ORPHANET_DG	22275001		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Bicuspid aortic valve	Bicuspid aortic valve	BEFREE	29162281, 30455415, 30796334, 30848080, 30963242		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Bicuspid aortic valve	Bicuspid aortic valve	CTD_human_DG	30455415		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Bicuspid aortic valve	Bicuspid aortic valve	HPO_DG			★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Bicuspid Aortic Valve Disease	Bicuspid aortic valve	Pubtator	30796334, 32748548	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Bone Diseases	Bone disease	Pubtator	29420098	Associate	★☆☆☆☆ Found in Text Mining only
Brachycephaly	Brachycephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	27113436		★☆☆☆☆ Found in Text Mining only
Carcinoma	Carcinoma	BEFREE	9892110		★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	27693511	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma of lung	Lung carcinoma	BEFREE	19047146, 28601662		★☆☆☆☆ Found in Text Mining only
Carcinoma Pancreatic Ductal	Pancreatic ductal carcinoma	Pubtator	21768661	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	24916699	Associate	★☆☆☆☆ Found in Text Mining only
Carpal Tunnel Syndrome	Carpal Tunnel Syndrome	GWASCAT_DG	30833571		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Chronic Obstructive Airway Disease	Chronic Obstructive Pulmonary Disease	BEFREE	15318814		★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	GWASCAT_DG	30510241, 31089142		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	27662660	Associate	★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal Neoplasms	GWASCAT_DG	30510241, 31089142		★☆☆☆☆ Found in Text Mining only
Craniosynostoses	Craniosynostosis	Pubtator	27606499, 30796334, 32499606, 36732661	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Craniosynostosis	Craniosynostosis	BEFREE	30088857, 30796334, 30963242, 31592950		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Craniosynostosis	Craniosynostosis	CTD_human_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Craniosynostosis	Craniosynostosis	HPO_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CRANIOSYNOSTOSIS 7	Craniosynostosis	UNIPROT_DG	27606499		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
CRANIOSYNOSTOSIS 7	Craniosynostosis	GENOMICS_ENGLAND_DG	28659821		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Craniosynostosis, Type 1	Craniosynostosis	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus Type 1	Diabetes mellitus, type 1	Pubtator	35058920	Associate	★☆☆☆☆ Found in Text Mining only
Esophageal Squamous Cell Carcinoma	Esophageal squamous cell carcinoma	Pubtator	15736400	Associate	★☆☆☆☆ Found in Text Mining only
Familial thoracic aortic aneurysm and aortic dissection	Thoracic Aortic Aneurysm And Aortic Dissection	GENOMICS_ENGLAND_DG			★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	BEFREE	29950561		★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	32744694	Associate	★☆☆☆☆ Found in Text Mining only
Heart Defects Congenital	Congenital heart defect	Pubtator	27218255, 34208845, 40715143	Associate	★☆☆☆☆ Found in Text Mining only
Heart Diseases	Heart Diseases	BEFREE	28121345		★☆☆☆☆ Found in Text Mining only
Hereditary hemochromatosis	Hereditary Hemochromatosis	BEFREE	22960056, 25392930		★☆☆☆☆ Found in Text Mining only
Hypertension	Hypertension	Pubtator	37451613	Associate	★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	BEFREE	27324164		★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypoplastic Left Heart Syndrome	Hypoplastic Left Heart Syndrome	HPO_DG			★☆☆☆☆ Found in Text Mining only
Intracranial Arteriovenous Malformations	Intracranial arteriovenous malformation	Pubtator	36198763	Associate	★☆☆☆☆ Found in Text Mining only
Iron Overload	Iron Overload	BEFREE	22960056		★☆☆☆☆ Found in Text Mining only
Keratoconus	Keratoconus	Pubtator	26015770	Associate	★☆☆☆☆ Found in Text Mining only
Language Development Disorders	Language development disorders	Pubtator	34208845, 36732661	Associate	★☆☆☆☆ Found in Text Mining only
Leukemia, Myelocytic, Acute	Leukemia	BEFREE	30177817		★☆☆☆☆ Found in Text Mining only
Liver carcinoma	Liver carcinoma	BEFREE	11408948, 27693511		★☆☆☆☆ Found in Text Mining only
Liver neoplasms	Liver neoplasms	BEFREE	27693511		★☆☆☆☆ Found in Text Mining only
Lung Diseases	Lung disease	Pubtator	32245290	Associate	★☆☆☆☆ Found in Text Mining only
Lung Neoplasms	Lung neoplasms	Pubtator	19047146, 26683690	Associate	★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	27113436		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of large intestine	Colorectal Neoplasms	GWASCAT_DG	30510241, 31089142		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of lung	Lung Cancer	BEFREE	19047146, 28601662		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of ovary	Ovarian cancer	BEFREE	11078792		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of pancreas	Pancreatic cancer	BEFREE	10049697		★☆☆☆☆ Found in Text Mining only
Malignant tumor of colon	Colonic Neoplasms	GWASCAT_DG	30510241, 31089142		★☆☆☆☆ Found in Text Mining only
Metopic synostosis	Metopic synostosis	GENOMICS_ENGLAND_DG	28659821		★☆☆☆☆ Found in Text Mining only
Metopic synostosis	Metopic synostosis	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Mucocutaneous Lymph Node Syndrome	Kawasaki disease	BEFREE	29344637		★☆☆☆☆ Found in Text Mining only
Mucocutaneous Lymph Node Syndrome	Kawasaki disease	Pubtator	29344637	Associate	★☆☆☆☆ Found in Text Mining only
Myeloid Leukemia, Chronic	Myeloid Leukemia	BEFREE	27716259		★☆☆☆☆ Found in Text Mining only
Non-Small Cell Lung Carcinoma	Lung carcinoma	BEFREE	19047146, 23284751		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	BEFREE	28121345		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	Pubtator	36528638	Associate	★☆☆☆☆ Found in Text Mining only
Osteitis Fibrosa Disseminata	Fibrous dysplasia	BEFREE	22450860		★☆☆☆☆ Found in Text Mining only
Osteoarthritis	Osteoarthritis	Pubtator	27208419	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Osteopenia	Osteopenia	BEFREE	29420098		★☆☆☆☆ Found in Text Mining only
Osteoporosis	Osteoporosis	BEFREE	19277452		★☆☆☆☆ Found in Text Mining only
Osteosarcoma	Osteosarcoma	Pubtator	39454801	Associate	★☆☆☆☆ Found in Text Mining only
Ovarian Neoplasms	Ovarian neoplasm	Pubtator	21984931	Associate	★☆☆☆☆ Found in Text Mining only
Pancreatic carcinoma	Pancreatic carcinoma	BEFREE	10049697		★☆☆☆☆ Found in Text Mining only
Periodontitis	Periodontitis	BEFREE	29420098		★☆☆☆☆ Found in Text Mining only
Periodontitis	Periodontitis	Pubtator	29420098	Associate	★☆☆☆☆ Found in Text Mining only
Polycystic Ovary Syndrome	Polycystic Ovary Syndrome	BEFREE	31735954		★☆☆☆☆ Found in Text Mining only
Polydactyly	Polydactyly	Pubtator	34953066	Associate	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	33174391	Associate	★☆☆☆☆ Found in Text Mining only
Radioulnar Synostosis	Radioulnar Synostosis	BEFREE	31138930, 31178591		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Radioulnar Synostosis	Radioulnar Synostosis	GENOMICS_ENGLAND_DG	31138930		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Renal glomerular disease	Renal Glomerular Disease	BEFREE	12397035		★☆☆☆☆ Found in Text Mining only
Scaphycephaly	Scaphocephaly	GENOMICS_ENGLAND_DG	28659821		★☆☆☆☆ Found in Text Mining only
Scaphycephaly	Scaphocephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Squamous cell carcinoma	Carcinoma	BEFREE	20462450		★☆☆☆☆ Found in Text Mining only
Squamous Cell Carcinoma of Head and Neck	Squamous cell carcinoma	Pubtator	20462450	Associate	★☆☆☆☆ Found in Text Mining only
Synostotic Anterior Plagiocephaly	Synostotic Anterior Plagiocephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Synostotic Posterior Plagiocephaly	Synostotic Posterior Plagiocephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Telangiectasia Hereditary Hemorrhagic	Hereditary hemorrhagic telangiectasia	Pubtator	37689549	Associate	★☆☆☆☆ Found in Text Mining only
Trigonocephaly	Trigonocephaly	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Urinary Bladder Neurogenic	Neurogenic bladder	Pubtator	35662268	Inhibit	★☆☆☆☆ Found in Text Mining only