EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4)

Gene

• Entrez ID: 440275
• Gene name: Eukaryotic translation initiation factor 2 alpha kinase 4
• Gene symbol: EIF2AK4
• Synonyms (NCBI Gene): GCN2, PVOD2
• Chromosome: 15
• Chromosome location: 15q15.1
• Summary: This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by bin

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs35480871	A>G	Conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant
rs202140402	C>T	Pathogenic	Coding sequence variant, stop gained
rs371276330	A>C	Likely-pathogenic	Intron variant
rs376877634	C>A,T	Pathogenic	Intron variant
rs587777102	T>-	Pathogenic-likely-pathogenic	Frameshift variant, coding sequence variant
rs587777103	C>T	Pathogenic	Stop gained, coding sequence variant
rs587777104	->G	Pathogenic	Frameshift variant, coding sequence variant
rs587777105	C>T	Pathogenic	Stop gained, coding sequence variant
rs587777106	G>A	Pathogenic	Coding sequence variant, missense variant
rs587777107	C>G,T	Pathogenic	Stop gained, coding sequence variant, missense variant
rs587777207	C>T	Pathogenic	Stop gained, coding sequence variant
rs587777208	C>T	Pathogenic	Stop gained, coding sequence variant
rs745339673	CAGA>-	Pathogenic	Frameshift variant, coding sequence variant
rs751247185	->CACT	Pathogenic	Frameshift variant, coding sequence variant
rs756315327	T>-	Likely-pathogenic	Stop gained, coding sequence variant
rs756902589	G>T	Pathogenic	Splice donor variant
rs757852728	T>G	Pathogenic	Missense variant, coding sequence variant
rs759101551	C>G,T	Pathogenic	Missense variant, stop gained, coding sequence variant
rs760842663	C>T	Pathogenic	Stop gained, coding sequence variant
rs767131900	CTGACCAACG>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs771359303	G>A	Likely-pathogenic	Missense variant, coding sequence variant
rs772487425	AAGAA>-	Pathogenic	Frameshift variant, coding sequence variant
rs774163084	C>G,T	Pathogenic	Stop gained, coding sequence variant, missense variant
rs774906916	C>T	Pathogenic	Coding sequence variant, missense variant
rs775819448	->G	Pathogenic	Frameshift variant, coding sequence variant
rs776140816	G>A,C	Pathogenic	Splice donor variant
rs886037661	G>A	Pathogenic	Splice acceptor variant
rs1085307439	TG>-	Pathogenic	Coding sequence variant, frameshift variant
rs1085307441	G>A	Pathogenic	Splice donor variant
rs1085307442	G>A	Pathogenic	Synonymous variant, coding sequence variant
rs1085307443	C>T	Pathogenic	Stop gained, coding sequence variant
rs1085307444	->T	Pathogenic	Coding sequence variant, frameshift variant
rs1085307445	GTAAGTGGCTTTC>TTCT	Pathogenic	Splice donor variant, intron variant
rs1159906680	A>G,T	Likely-pathogenic	Coding sequence variant, missense variant
rs1181863323	->T	Likely-pathogenic	Coding sequence variant, stop gained
rs1291600097	G>C	Likely-pathogenic	Coding sequence variant, missense variant
rs1327297003	T>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1555417104	GAAAG>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1595402535	->A	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1595403854	T>G	Likely-pathogenic	Coding sequence variant, missense variant
rs1595414835	C>G	Likely-pathogenic	Coding sequence variant, missense variant
rs1595418005	G>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1595431276	T>G	Likely-pathogenic	Coding sequence variant, missense variant
rs1595437286	->T	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1595539403	A>G	Pathogenic	Splice acceptor variant
rs1595541066	->A	Pathogenic	Coding sequence variant, frameshift variant
rs1595552181	CT>-	Likely-pathogenic	Coding sequence variant, frameshift variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT572593	hsa-miR-4282	PAR-CLIP	20371350
MIRT572594	hsa-miR-3617-5p	PAR-CLIP	20371350
MIRT572592	hsa-miR-641	PAR-CLIP	20371350
MIRT572591	hsa-miR-208a-3p	PAR-CLIP	20371350
MIRT572590	hsa-miR-208b-3p	PAR-CLIP	20371350
MIRT572589	hsa-miR-499a-5p	PAR-CLIP	20371350
MIRT572587	hsa-miR-3658	PAR-CLIP	20371350
MIRT572588	hsa-miR-7856-5p	PAR-CLIP	20371350
MIRT572593	hsa-miR-4282	PAR-CLIP	20371350
MIRT572594	hsa-miR-3617-5p	PAR-CLIP	20371350
MIRT572592	hsa-miR-641	PAR-CLIP	20371350
MIRT572591	hsa-miR-208a-3p	PAR-CLIP	20371350
MIRT572590	hsa-miR-208b-3p	PAR-CLIP	20371350
MIRT572589	hsa-miR-499a-5p	PAR-CLIP	20371350
MIRT572587	hsa-miR-3658	PAR-CLIP	20371350
MIRT572588	hsa-miR-7856-5p	PAR-CLIP	20371350
MIRT956664	hsa-miR-1182	CLIP-seq
MIRT956665	hsa-miR-1197	CLIP-seq
MIRT956666	hsa-miR-122	CLIP-seq
MIRT956667	hsa-miR-1267	CLIP-seq
MIRT956668	hsa-miR-145	CLIP-seq
MIRT956669	hsa-miR-193a-5p	CLIP-seq
MIRT956670	hsa-miR-208a	CLIP-seq
MIRT956671	hsa-miR-208b	CLIP-seq
MIRT956672	hsa-miR-3120-5p	CLIP-seq
MIRT956673	hsa-miR-3194-3p	CLIP-seq
MIRT956674	hsa-miR-3199	CLIP-seq
MIRT956675	hsa-miR-3617	CLIP-seq
MIRT956676	hsa-miR-3674	CLIP-seq
MIRT956677	hsa-miR-431	CLIP-seq
MIRT956678	hsa-miR-4438	CLIP-seq
MIRT956679	hsa-miR-4463	CLIP-seq
MIRT956680	hsa-miR-4494	CLIP-seq
MIRT956681	hsa-miR-4646-3p	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT956683	hsa-miR-4712-5p	CLIP-seq
MIRT956684	hsa-miR-4733-5p	CLIP-seq
MIRT956685	hsa-miR-4795-3p	CLIP-seq
MIRT956686	hsa-miR-499-5p	CLIP-seq
MIRT956687	hsa-miR-5095	CLIP-seq
MIRT956688	hsa-miR-513a-3p	CLIP-seq
MIRT956689	hsa-miR-516b	CLIP-seq
MIRT956690	hsa-miR-543	CLIP-seq
MIRT956691	hsa-miR-577	CLIP-seq
MIRT956692	hsa-miR-770-5p	CLIP-seq
MIRT956693	hsa-miR-885-5p	CLIP-seq
MIRT1983313	hsa-miR-1178	CLIP-seq
MIRT1983314	hsa-miR-1184	CLIP-seq
MIRT1983315	hsa-miR-1273f	CLIP-seq
MIRT956669	hsa-miR-193a-5p	CLIP-seq
MIRT1983316	hsa-miR-3155	CLIP-seq
MIRT1983317	hsa-miR-3155b	CLIP-seq
MIRT956677	hsa-miR-431	CLIP-seq
MIRT1983318	hsa-miR-4418	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT1983319	hsa-miR-484	CLIP-seq
MIRT1983320	hsa-miR-509-3-5p	CLIP-seq
MIRT1983321	hsa-miR-509-5p	CLIP-seq
MIRT956690	hsa-miR-543	CLIP-seq
MIRT1983322	hsa-miR-615-5p	CLIP-seq
MIRT956693	hsa-miR-885-5p	CLIP-seq
MIRT1983314	hsa-miR-1184	CLIP-seq
MIRT2218507	hsa-miR-1200	CLIP-seq
MIRT956666	hsa-miR-122	CLIP-seq
MIRT2218508	hsa-miR-1227	CLIP-seq
MIRT2218509	hsa-miR-24	CLIP-seq
MIRT2218510	hsa-miR-2467-5p	CLIP-seq
MIRT2218511	hsa-miR-3129-3p	CLIP-seq
MIRT2218512	hsa-miR-3188	CLIP-seq
MIRT956674	hsa-miR-3199	CLIP-seq
MIRT2218513	hsa-miR-3975	CLIP-seq
MIRT2218514	hsa-miR-4324	CLIP-seq
MIRT1983318	hsa-miR-4418	CLIP-seq
MIRT956678	hsa-miR-4438	CLIP-seq
MIRT956679	hsa-miR-4463	CLIP-seq
MIRT956680	hsa-miR-4494	CLIP-seq
MIRT2218515	hsa-miR-455-5p	CLIP-seq
MIRT956681	hsa-miR-4646-3p	CLIP-seq
MIRT2218516	hsa-miR-4649-3p	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT2218517	hsa-miR-4714-3p	CLIP-seq
MIRT2218518	hsa-miR-4715-3p	CLIP-seq
MIRT2218519	hsa-miR-485-5p	CLIP-seq
MIRT1983320	hsa-miR-509-3-5p	CLIP-seq
MIRT956687	hsa-miR-5095	CLIP-seq
MIRT1983321	hsa-miR-509-5p	CLIP-seq
MIRT2218520	hsa-miR-544b	CLIP-seq
MIRT2218521	hsa-miR-640	CLIP-seq
MIRT1983314	hsa-miR-1184	CLIP-seq
MIRT1983318	hsa-miR-4418	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT1983320	hsa-miR-509-3-5p	CLIP-seq
MIRT1983321	hsa-miR-509-5p	CLIP-seq
MIRT956689	hsa-miR-516b	CLIP-seq
MIRT1983313	hsa-miR-1178	CLIP-seq
MIRT956666	hsa-miR-122	CLIP-seq
MIRT2218508	hsa-miR-1227	CLIP-seq
MIRT1983315	hsa-miR-1273f	CLIP-seq
MIRT956669	hsa-miR-193a-5p	CLIP-seq
MIRT2521967	hsa-miR-3074-5p	CLIP-seq
MIRT2218511	hsa-miR-3129-3p	CLIP-seq
MIRT1983316	hsa-miR-3155	CLIP-seq
MIRT1983317	hsa-miR-3155b	CLIP-seq
MIRT956674	hsa-miR-3199	CLIP-seq
MIRT2521968	hsa-miR-3663-5p	CLIP-seq
MIRT2521969	hsa-miR-371-5p	CLIP-seq
MIRT2521970	hsa-miR-371b-5p	CLIP-seq
MIRT2521971	hsa-miR-3976	CLIP-seq
MIRT2521972	hsa-miR-4274	CLIP-seq
MIRT956677	hsa-miR-431	CLIP-seq
MIRT2521973	hsa-miR-4312	CLIP-seq
MIRT956678	hsa-miR-4438	CLIP-seq
MIRT956679	hsa-miR-4463	CLIP-seq
MIRT956680	hsa-miR-4494	CLIP-seq
MIRT2218515	hsa-miR-455-5p	CLIP-seq
MIRT956681	hsa-miR-4646-3p	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT2218518	hsa-miR-4715-3p	CLIP-seq
MIRT2521974	hsa-miR-4722-3p	CLIP-seq
MIRT2521975	hsa-miR-4735-5p	CLIP-seq
MIRT2521976	hsa-miR-4775	CLIP-seq
MIRT1983319	hsa-miR-484	CLIP-seq
MIRT2521977	hsa-miR-498	CLIP-seq
MIRT956687	hsa-miR-5095	CLIP-seq
MIRT2521978	hsa-miR-590-3p	CLIP-seq
MIRT1983322	hsa-miR-615-5p	CLIP-seq
MIRT1983313	hsa-miR-1178	CLIP-seq
MIRT956666	hsa-miR-122	CLIP-seq
MIRT2218508	hsa-miR-1227	CLIP-seq
MIRT1983315	hsa-miR-1273f	CLIP-seq
MIRT956669	hsa-miR-193a-5p	CLIP-seq
MIRT2218511	hsa-miR-3129-3p	CLIP-seq
MIRT1983316	hsa-miR-3155	CLIP-seq
MIRT1983317	hsa-miR-3155b	CLIP-seq
MIRT956674	hsa-miR-3199	CLIP-seq
MIRT2521968	hsa-miR-3663-5p	CLIP-seq
MIRT2521969	hsa-miR-371-5p	CLIP-seq
MIRT2521970	hsa-miR-371b-5p	CLIP-seq
MIRT2521971	hsa-miR-3976	CLIP-seq
MIRT2521972	hsa-miR-4274	CLIP-seq
MIRT956677	hsa-miR-431	CLIP-seq
MIRT956678	hsa-miR-4438	CLIP-seq
MIRT956679	hsa-miR-4463	CLIP-seq
MIRT956680	hsa-miR-4494	CLIP-seq
MIRT2218515	hsa-miR-455-5p	CLIP-seq
MIRT956681	hsa-miR-4646-3p	CLIP-seq
MIRT956682	hsa-miR-4704-3p	CLIP-seq
MIRT2218518	hsa-miR-4715-3p	CLIP-seq
MIRT2521975	hsa-miR-4735-5p	CLIP-seq
MIRT2521976	hsa-miR-4775	CLIP-seq
MIRT1983319	hsa-miR-484	CLIP-seq
MIRT2521977	hsa-miR-498	CLIP-seq
MIRT956687	hsa-miR-5095	CLIP-seq
MIRT2521978	hsa-miR-590-3p	CLIP-seq
MIRT1983322	hsa-miR-615-5p	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000049	Function	TRNA binding	IEA
GO:0000049	Function	TRNA binding	ISS
GO:0000077	Process	DNA damage checkpoint signaling	IEA
GO:0000166	Function	Nucleotide binding	IEA
GO:0002230	Process	Positive regulation of defense response to virus by host	ISS
GO:0002250	Process	Adaptive immune response	IEA
GO:0002286	Process	T cell activation involved in immune response	ISS
GO:0002376	Process	Immune system process	IEA
GO:0002821	Process	Positive regulation of adaptive immune response	ISS
GO:0003723	Function	RNA binding	IEA
GO:0004672	Function	Protein kinase activity	IEA
GO:0004674	Function	Protein serine/threonine kinase activity	IEA
GO:0004674	Function	Protein serine/threonine kinase activity	ISS
GO:0004694	Function	Eukaryotic translation initiation factor 2alpha kinase activity	IBA
GO:0004694	Function	Eukaryotic translation initiation factor 2alpha kinase activity	IDA	25329545
GO:0004694	Function	Eukaryotic translation initiation factor 2alpha kinase activity	IEA
GO:0004694	Function	Eukaryotic translation initiation factor 2alpha kinase activity	IMP	25329545
GO:0004694	Function	Eukaryotic translation initiation factor 2alpha kinase activity	ISS	10504407
GO:0005524	Function	ATP binding	IEA
GO:0005634	Component	Nucleus	IBA
GO:0005737	Component	Cytoplasm	IBA
GO:0005737	Component	Cytoplasm	IEA
GO:0005737	Component	Cytoplasm	ISS
GO:0005829	Component	Cytosol	IBA
GO:0006413	Process	Translational initiation	IDA	16289705
GO:0006417	Process	Regulation of translation	IEA
GO:0006446	Process	Regulation of translational initiation	ISS
GO:0006468	Process	Protein phosphorylation	ISS
GO:0007399	Process	Nervous system development	IEA
GO:0007612	Process	Learning	ISS
GO:0007616	Process	Long-term memory	ISS
GO:0010998	Process	Regulation of translational initiation by eIF2 alpha phosphorylation	IMP	26102367
GO:0010998	Process	Regulation of translational initiation by eIF2 alpha phosphorylation	ISS
GO:0016301	Function	Kinase activity	IEA
GO:0016740	Function	Transferase activity	IEA
GO:0019081	Process	Viral translation	ISS
GO:0022626	Component	Cytosolic ribosome	ISS
GO:0032057	Process	Negative regulation of translational initiation in response to stress	IBA
GO:0032057	Process	Negative regulation of translational initiation in response to stress	ISS
GO:0032792	Process	Negative regulation of CREB transcription factor activity	ISS
GO:0034198	Process	Cellular response to amino acid starvation	IBA
GO:0034198	Process	Cellular response to amino acid starvation	IEA
GO:0034198	Process	Cellular response to amino acid starvation	IMP	25329545
GO:0034644	Process	Cellular response to UV	ISS
GO:0034976	Process	Response to endoplasmic reticulum stress	IEA
GO:0044828	Process	Host-mediated suppression of viral genome replication	ISS
GO:0045665	Process	Negative regulation of neuron differentiation	ISS
GO:0045947	Process	Negative regulation of translational initiation	ISS
GO:0046777	Process	Protein autophosphorylation	ISS
GO:0051607	Process	Defense response to virus	IEA
GO:0051726	Process	Regulation of cell cycle	IEA
GO:0060259	Process	Regulation of feeding behavior	ISS
GO:0070417	Process	Cellular response to cold	IMP	25329545
GO:0071264	Process	Positive regulation of translational initiation in response to starvation	ISS
GO:0106310	Function	Protein serine kinase activity	IEA
GO:0140469	Process	GCN2-mediated signaling	IDA	25329545
GO:0140469	Process	GCN2-mediated signaling	IEA
GO:0140469	Process	GCN2-mediated signaling	IMP	26102367
GO:0140469	Process	GCN2-mediated signaling	ISS
GO:1900273	Process	Positive regulation of long-term synaptic potentiation	ISS
GO:1990138	Process	Neuron projection extension	ISS

Other IDs

• MIM: 609280
• HGNC: 19687
• e!Ensembl: ENSG00000128829

Protein

• UniProt ID: Q9P2K8
• Protein name: eIF-2-alpha kinase GCN2 (EC 2.7.11.1) (Eukaryotic translation initiation factor 2-alpha kinase 4) (GCN2-like protein)
• Protein function: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability (PubMed:25329545, PubMed:32610081). Plays a role as an ac
• PDB: 6N3L, 6N3N, 6N3O, 7E2K, 7E2M, 7QQ6, 7QWK, 8T7T
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF05773	RWD	21 → 134	RWD domain	Domain
  PF00069	Pkinase	325 → 539	Protein kinase domain	Domain
  PF00069	Pkinase	590 → 662	Protein kinase domain	Domain
  PF00069	Pkinase	788 → 1001	Protein kinase domain	Domain
  PF13393	tRNA-synt_His	1056 → 1381	Histidyl-tRNA synthetase	Domain
  PF12745	HGTP_anticodon2	1393 → 1648	Anticodon binding domain of tRNAs	Domain

• Tissue specificity: TISSUE SPECIFICITY: Widely expressed (PubMed:10504407). Expressed in lung, smooth muscle cells and macrophages (PubMed:24292273). {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:24292273}.
• Sequence:

  MAGGRGAPGRGRDEPPESYPQRQDHELQALEAIYGADFQDLRPDACGPVKEPPEINLVLY
  PQGLTGEEVYVKVDLRVKCPPTYPDVVPEIELKNAKGLSNESVNLLKSRLEELAKKHCGE
  VMIFELAYHVQSFLSEHNKPPPKSFHEEMLERRAQEEQQRLLEAKRKEEQEQREILHEIQ
  RRKEEIKEEKKRKEMAKQERLEIASLSNQDHTSKKDPGGHRTAAILHGGSPDFVGNGKHR
  ANSSGRSRRERQYSVCNSEDSPGSCEILYFNMGSPDQLMVHKGKCIGSDEQLGKLVYNAL
  ETATGGFVLLYEWVLQWQKKMGPFLTSQEKEKIDKCKKQIQGTETEFNSLVKLSHPNVVR
  YLAMNLKEQDDSIVVDILVEHISGVSLAAHLSHSGPIPVHQLRRYTAQLLSGLDYLHSNS
  VVHKVLSASNVLVDAEGTVKITDYSISKRLADICKEDVFEQTRVRFSDNALPYKTGKKGD
  VWRLGLLLLSLSQGQECGEYPVTIPSDLPADFQDFLKKCVCLDDKERWSPQQLLKHSFIN
  PQPKMPLVEQSPEDSEGQDYVETVIPSNRLPSAAFFSETQRQFSRYFIEFEELQLLGKGA
  FGAVIKVQNKLDGCCYAVKRIPINPASRQFRRIKGEVTLLSRLHHENIVRYYNAWIERHE
  RPAGPGTPPPDSGPLAKDDRAARGQPASDTDGLDSVEAAAPPPILSSSVEWSTSGERSAS
  ARFPATGPGSSDDEDDDEDEHGGVFSQSFLPASDSESDIIFDNEDENSKSQNQDEDCNEK
  NGCHESEPSVTTEAVHYLYIQMEYCEKSTLRDTIDQGLYRDTVRLWRLFREILDGLAYIH
  EKGMIHRDLKPVNIFLDSDDHVKIGDFGLATDHLAFSADSKQDDQTGDLIKSDPSGHLTG
  MVGTALYVSPEVQGSTKSAYNQKVDLFSLGIIFFEMSYHPMVTASERIFVLNQLRDPTSP
  KFPEDFDDGEHAKQKSVISWLLNHDPAKRPTATELLKSELLPPPQMEESELHEVLHHTLT
  NVDGKAYRTMMAQIFSQRISPAIDYTYDSDILKGNFSIRTAKMQQHVCETIIRIFKRHGA
  VQLCTPLLLPRNRQIYEHNEAALFMDHSGMLVMLPFDLRIPFARYVARNNILNLKRYCIE
  RVFRPRKLDRFHPKELLECAFDIVTSTTNSFLPTAEIIYTIYEIIQEFPALQERNYSIYL
  NHTMLLKAILLHCGIPEDKLSQVYIILYDAVTEKLTRREVEAKFCNLSLSSNSLCRLYKF
  IEQKGDLQDLMPTINSLIKQKTGIAQLVKYGLKDLEEVVGLLKKLGIKLQVLINLGLVYK
  VQQHNGIIFQFVAFIKRRQRAVPEILAAGGRYDLLIPQFRGPQALGPVPTAIGVSIAIDK
  ISAAVLNMEESVTISSCDLLVVSVGQMSMSRAINLTQKLWTAGITAEIMYDWSQSQEELQ
  EYCRHHEITYVALVSDKEGSHVKVKSFEKERQTEKRVLETELVDHVLQKLRTKVTDERNG
  REASDNLAVQNLKGSFSNASGLFEIHGATVVPIVSVLAPEKLSASTRRRYETQVQTRLQT
  SLANLHQKSSEIEILAVDLPKETILQFLSLEWDADEQAFNTTVKQLLSRLPKQRYLKLVC
  DEIYNIKVEKKVSVLFLYSYRDDYYRILF

• Sequence length: 1649

Pathways

KEGG:

Autophagy - animal
Hepatitis C
Measles
Herpes simplex virus 1 infection

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
EIF2AK4-related disorder	Likely pathogenic; Pathogenic	rs2504564381, rs2504537554, rs2034558794	RCV003402103 RCV003402915 RCV003924405	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Familial pulmonary capillary hemangiomatosis	Pathogenic; Likely pathogenic	rs587777102, rs587777103, rs587777104, rs587777105, rs587777106, rs587777107, rs775819448, rs587777207, rs587777208, rs886037661, rs776140816, rs770279669, rs772487425, rs2504573137, rs1085307439, rs202140402, rs376877634, rs757852728, rs751247185, rs1085307441, rs774163084, rs759101551, rs1085307442, rs1085307443, rs774906916, rs756902589, rs1085307444, rs1085307445, rs1595541066, rs1595552181, rs1595402535, rs1291600097, rs1595403854, rs1595414835, rs1595418005, rs767131900, rs760842663, rs771359303, rs1159906680, rs1595431276, rs1181863323, rs1595437286, rs745339673, rs1595539403, rs371276330	RCV000083306 RCV000083307 RCV000083308 RCV000083309 RCV000083310 RCV000083311 RCV000087755 RCV000087756 RCV000087757 RCV000087758 RCV001783194 RCV005356167 RCV000488528 RCV003337736 RCV000488788 RCV000488705 RCV000488704 RCV000488861 RCV000488596 RCV000488727 RCV000488486 RCV000488559 RCV000488748 RCV000488475 RCV000488662 RCV000488503 RCV000488628 RCV000488784 RCV000488522 RCV001003761 RCV001003762 RCV001003763 RCV001003764 RCV001003765 RCV001003766 RCV001003767 RCV001003768 RCV001003769 RCV001003770 RCV001003771 RCV001003772 RCV001003773 RCV001003774 RCV001003775 RCV001003759 RCV001003760	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Pulmonary arterial hypertension	Pathogenic; Likely pathogenic	rs2504524056, rs1566988788, rs756315327	RCV002285235 RCV002285245 RCV001003776	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pulmonary venoocclusive disease 1	Likely pathogenic	rs1327297003	RCV000826105	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute myeloid leukemia	Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
AMINO ACID METABOLISM, INBORN ERRORS	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cholangiocarcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Colon adenocarcinoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEMENTIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DISORDERS INVOLVING THE IMMUNE MECHANISM	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
EBV-positive nodal T- and NK-cell lymphoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ENDOMETRIAL CANCER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ENDOMETRIAL CARCINOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ENDOMETRIAL ENDOMETRIOID CARCINOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ENDOMETRIAL NEOPLASM	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
FAMILIAL PRIMARY PULMONARY HYPERTENSION	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HERITABLE PULMONARY ARTERIAL HYPERTENSION	—	CTD, Orphanet CTD, Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HYPERTENSION	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HYPERTENSION, PULMONARY	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
IMMUNE SYSTEM DISEASES	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Lung cancer	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of esophagus	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of urinary bladder	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MYOPATHY	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thymoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thyroid cancer, nonmedullary, 1	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uveal melanoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acute lymphocytic leukemia	Lymphocytic Leukemia	BEFREE	30061420, 30364637, 31620240		★☆☆☆☆ Found in Text Mining only
Adult Acute Lymphocytic Leukemia	Lymphocytic Leukemia	BEFREE	30061420, 31620240		★☆☆☆☆ Found in Text Mining only
Alzheimer Disease	Alzheimer disease	Pubtator	33798591	Associate	★☆☆☆☆ Found in Text Mining only
Amino Acid Metabolism, Inborn Errors	Disorder of amino acid metabolism	CTD_human_DG	21239484		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Amino Acid Metabolism, Inherited Disorders	Inherited Errors of Amino Acid Metabolism	CTD_human_DG	21239484		★☆☆☆☆ Found in Text Mining only
Brain Neoplasms	Brain Neoplasms	BEFREE	31844909		★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	33910445, 35839757	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	29865032	Associate	★☆☆☆☆ Found in Text Mining only
Cardiomyopathy, Familial Idiopathic	Cardiomyopathy	BEFREE	30389499		★☆☆☆☆ Found in Text Mining only
Childhood Acute Lymphoblastic Leukemia	Lymphoblastic Leukemia	BEFREE	30061420, 31620240		★☆☆☆☆ Found in Text Mining only
Chronic Kidney Diseases	Kidney Disease	BEFREE	28894140		★☆☆☆☆ Found in Text Mining only
Colonic Neoplasms	Colonic neoplasm	Pubtator	37452637	Associate	★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	BEFREE	25892863, 31685988		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	22435535, 25892863, 37452637	Associate	★☆☆☆☆ Found in Text Mining only
Coronary Arteriosclerosis	Coronary Arteriosclerosis	BEFREE	31632531		★☆☆☆☆ Found in Text Mining only
Crohn Disease	Crohn disease	Pubtator	26986695	Associate	★☆☆☆☆ Found in Text Mining only
Cutaneous Melanoma	Melanoma	BEFREE	31836669		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	BEFREE	30389499		★☆☆☆☆ Found in Text Mining only
Endometrial Carcinoma	Endometrial carcinoma	GWASCAT_DG	27135401, 30093612		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial primary pulmonary hypertension	Pulmonary Hypertension	ORPHANET_DG	25512148		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial primary pulmonary hypertension	Pulmonary Hypertension	BEFREE	27809840, 27884767		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial primary pulmonary hypertension	Pulmonary Hypertension	GENOMICS_ENGLAND_DG	29844075		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial Primary Pulmonary Hypertension	Pulmonary hypertension	Pubtator	34731104	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial pulmonary arterial hypertension	Pulmonary arterial hypertension	ORPHANET_DG	25512148		★☆☆☆☆ Found in Text Mining only
Fatty Liver	Fatty Liver	BEFREE	30006154		★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	BEFREE	31844909		★☆☆☆☆ Found in Text Mining only
Glioblastoma Multiforme	Glioblastoma	BEFREE	31844909		★☆☆☆☆ Found in Text Mining only
Hair Diseases	Hair Diseases	CTD_human_DG	21239484		★☆☆☆☆ Found in Text Mining only
Hepatic Veno Occlusive Disease	Hepatic veno occlusive disease	Pubtator	27809840	Associate	★☆☆☆☆ Found in Text Mining only
Heritable pulmonary arterial hypertension	Heritable Pulmonary Arterial Hypertension	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hyperinsulinism	Hyperinsulinism	BEFREE	28052287		★☆☆☆☆ Found in Text Mining only
Hypertension Pulmonary	Pulmonary hypertension	Pubtator	31636247, 31711431	Associate	★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	BEFREE	24292273, 27884767, 31202500, 31711431		★☆☆☆☆ Found in Text Mining only
Idiopathic pulmonary arterial hypertension	Pulmonary arterial hypertension	BEFREE	25512148, 27809840, 27884767, 31711431		★☆☆☆☆ Found in Text Mining only
Idiopathic pulmonary arterial hypertension	Pulmonary arterial hypertension	GENOMICS_ENGLAND_DG	29844075		★☆☆☆☆ Found in Text Mining only
Idiopathic pulmonary arterial hypertension	Pulmonary arterial hypertension	HPO_DG			★☆☆☆☆ Found in Text Mining only
Idiopathic pulmonary hypertension	Pulmonary Hypertension	BEFREE	27884767		★☆☆☆☆ Found in Text Mining only
Idiopathic pulmonary hypertension	Pulmonary Hypertension	GENOMICS_ENGLAND_DG	29844075		★☆☆☆☆ Found in Text Mining only
Immune System Diseases	Immune System Diseases	CTD_human_DG	21239484		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Immunologic Deficiency Syndromes	Immunologic Deficiency Syndromes	BEFREE	28465428		★☆☆☆☆ Found in Text Mining only
Kidney Neoplasms	Kidney neoplasm	Pubtator	29865032	Associate	★☆☆☆☆ Found in Text Mining only
leukemia	Leukemia	BEFREE	30364637		★☆☆☆☆ Found in Text Mining only
Leukodystrophy	Leukodystrophy	BEFREE	24019515		★☆☆☆☆ Found in Text Mining only
Lung Diseases	Lung disease	Pubtator	32461209, 32471403, 36898579	Associate	★☆☆☆☆ Found in Text Mining only
Lung Neoplasms	Lung neoplasms	Pubtator	30158316	Associate	★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus, Systemic	Lupus Erythematosus	BEFREE	29080553		★☆☆☆☆ Found in Text Mining only
Lymphatic Metastasis	Lymphatic metastasis	Pubtator	29865032	Stimulate	★☆☆☆☆ Found in Text Mining only
Malignant Glioma	Glioma	BEFREE	31844909		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	23908598, 30061420, 30626938, 31620240		★☆☆☆☆ Found in Text Mining only
melanoma	Melanoma	BEFREE	26082174, 31836669		★☆☆☆☆ Found in Text Mining only
Memory dysfunction	Memory Disorders	BEFREE	23933749		★☆☆☆☆ Found in Text Mining only
Metabolic Diseases	Metabolic Diseases	BEFREE	29321774		★☆☆☆☆ Found in Text Mining only
Mitochondrial Diseases	Mitochondrial disease	Pubtator	27708226	Associate	★☆☆☆☆ Found in Text Mining only
Mitochondrial Diseases	Mitochondrial disease	Pubtator	30380689	Stimulate	★☆☆☆☆ Found in Text Mining only
Myocardial Infarction	Myocardial Infarction	BEFREE	31632531		★☆☆☆☆ Found in Text Mining only
Myocardial Ischemia	Myocardial Ischemia	BEFREE	31632531		★☆☆☆☆ Found in Text Mining only
Myopathy	Myopathy	CTD_human_DG	21239484		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Neoplasms	Neoplasms	BEFREE	26123823, 28557618, 29865032, 31685988, 31836669		★☆☆☆☆ Found in Text Mining only
Non-alcoholic Fatty Liver Disease	Non-Alcoholic Fatty Liver Disease	BEFREE	30006154		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	BEFREE	24827717, 31166980		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	Pubtator	24827717	Associate	★☆☆☆☆ Found in Text Mining only
Papillary Renal Cell Carcinoma	Papillary Renal Carcinoma	BEFREE	29865032		★☆☆☆☆ Found in Text Mining only
Pulmonary arterial hypertension	Pulmonary arterial hypertension	BEFREE	25512148, 27809840, 27884767, 31711431		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pulmonary Arterial Hypertension	Pulmonary arterial hypertension	Pubtator	27809840, 30285736, 33066286, 35346192, 36653758	Associate	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pulmonary arterial hypertension	Pulmonary arterial hypertension	GENOMICS_ENGLAND_DG	29844075		★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pulmonary arterial hypertension	Pulmonary arterial hypertension	HPO_DG			★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pulmonary capillary hemangiomatosis	Pulmonary capillary hemangiomatosis	BEFREE	24135949, 25159282, 25512148, 27884767, 29743074, 31711431		★☆☆☆☆ Found in Text Mining only
Pulmonary capillary hemangiomatosis	Pulmonary capillary hemangiomatosis	ORPHANET_DG	24135949		★☆☆☆☆ Found in Text Mining only
Pulmonary capillary hemangiomatosis	Pulmonary capillary hemangiomatosis	Orphanet			★☆☆☆☆ Found in Text Mining only
Pulmonary capillary hemangiomatosis	Pulmonary capillary hemangiomatosis	GENOMICS_ENGLAND_DG	29844075		★☆☆☆☆ Found in Text Mining only
Pulmonary capillary hemangiomatosis	Pulmonary capillary hemangiomatosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Pulmonary Veno-Occlusive Disease (disorder)	Pulmonary venoocclusive disease	BEFREE	24292273, 25159282, 25512148, 27684876, 28118962, 28697925, 29108819, 29229098, 29743074, 30679663, 31202500		★☆☆☆☆ Found in Text Mining only
Pulmonary Veno-Occlusive Disease (disorder)	Pulmonary venoocclusive disease	CTD_human_DG	24292273		★☆☆☆☆ Found in Text Mining only
Pulmonary Veno-Occlusive Disease (disorder)	Pulmonary venoocclusive disease	ORPHANET_DG	24292273		★☆☆☆☆ Found in Text Mining only
Pulmonary Veno-Occlusive Disease (disorder)	Pulmonary venoocclusive disease	GENOMICS_ENGLAND_DG	29844075		★☆☆☆☆ Found in Text Mining only
Pulmonary venoocclusive disease	Pulmonary venoocclusive disease	Orphanet			★☆☆☆☆ Found in Text Mining only
PULMONARY VENOOCCLUSIVE DISEASE 1, AUTOSOMAL DOMINANT	Pulmonary venoocclusive disease	BEFREE	24292273, 26541523, 26699722, 27009171, 27684876, 27884767, 28697925, 29108819, 29743074, 30285736, 30926335, 31202500		★☆☆☆☆ Found in Text Mining only
PULMONARY VENOOCCLUSIVE DISEASE 2, AUTOSOMAL RECESSIVE	Pulmonary venoocclusive disease	CLINVAR_DG	24135949, 24292273, 25512148		★☆☆☆☆ Found in Text Mining only
PULMONARY VENOOCCLUSIVE DISEASE 2, AUTOSOMAL RECESSIVE	Pulmonary venoocclusive disease	UNIPROT_DG	24135949, 24292273		★☆☆☆☆ Found in Text Mining only
PULMONARY VENOOCCLUSIVE DISEASE 2, AUTOSOMAL RECESSIVE	Pulmonary venoocclusive disease	GENOMICS_ENGLAND_DG	29844075		★☆☆☆☆ Found in Text Mining only
Sarcoma	Sarcoma	BEFREE	26123823		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Schizophrenia	Schizophrenia	BEFREE	24751813		★☆☆☆☆ Found in Text Mining only
Situs Inversus	Situs Inversus	BEFREE	28465428		★☆☆☆☆ Found in Text Mining only
Sjogren's Syndrome	Sjogren syndrome	Pubtator	36653758	Associate	★☆☆☆☆ Found in Text Mining only
Steatohepatitis	Fatty Liver	BEFREE	30006154		★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	27708226, 37260027	Associate	★☆☆☆☆ Found in Text Mining only
Triple Negative Breast Neoplasms	Triple negative breast cancer	Pubtator	37834012	Associate	★☆☆☆☆ Found in Text Mining only