CA4 (carbonic anhydrase 4)

Gene

• Entrez ID: 762
• Gene name: Carbonic anhydrase 4
• Gene symbol: CA4
• Synonyms (NCBI Gene): CAIV, Car4, RP17
• Chromosome: 17
• Chromosome location: 17q23.1
• Summary: Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption,

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs104894559	C>T	Pathogenic	Non coding transcript variant, coding sequence variant, genic upstream transcript variant, upstream transcript variant, missense variant
rs121434551	C>A,T	Pathogenic	Coding sequence variant, non coding transcript variant, missense variant
rs121434552	G>A	Pathogenic	5 prime UTR variant, coding sequence variant, non coding transcript variant, missense variant
rs185658468	A>T	Uncertain-significance, conflicting-interpretations-of-pathogenicity	Missense variant, non coding transcript variant, coding sequence variant
rs201580764	C>A,T	Conflicting-interpretations-of-pathogenicity	Non coding transcript variant, coding sequence variant, missense variant
rs1597993822	A>-	Likely-pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0004089	Function	Carbonate dehydratase activity	IBA
GO:0004089	Function	Carbonate dehydratase activity	IEA
GO:0004089	Function	Carbonate dehydratase activity	TAS	1311094
GO:0005515	Function	Protein binding	IPI	15563508
GO:0005791	Component	Rough endoplasmic reticulum	IDA	17409381
GO:0005793	Component	Endoplasmic reticulum-Golgi intermediate compartment	IDA	17409381
GO:0005794	Component	Golgi apparatus	IDA	17409381
GO:0005802	Component	Trans-Golgi network	IDA	17409381
GO:0005886	Component	Plasma membrane	IBA
GO:0005886	Component	Plasma membrane	IDA	15563508
GO:0005886	Component	Plasma membrane	IEA
GO:0005886	Component	Plasma membrane	TAS
GO:0008270	Function	Zinc ion binding	IEA
GO:0009897	Component	External side of plasma membrane	IDA	17409381
GO:0009986	Component	Cell surface	IDA	15563508
GO:0015701	Process	Bicarbonate transport	IMP	15563508
GO:0016020	Component	Membrane	IEA
GO:0016020	Component	Membrane	TAS	6811592
GO:0016323	Component	Basolateral plasma membrane	IDA	17409381
GO:0016324	Component	Apical plasma membrane	IDA	17409381
GO:0016829	Function	Lyase activity	IEA
GO:0030658	Component	Transport vesicle membrane	IDA	17409381
GO:0030667	Component	Secretory granule membrane	IDA	17409381
GO:0031526	Component	Brush border membrane	IDA	17409381
GO:0046872	Function	Metal ion binding	IEA
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	17409381
GO:0070062	Component	Extracellular exosome	HDA	19056867, 20458337, 23533145
GO:0070062	Component	Extracellular exosome	IDA	15326289
GO:0098552	Component	Side of membrane	IEA

Other IDs

• MIM: 114760
• HGNC: 1375
• e!Ensembl: ENSG00000167434

Protein

• UniProt ID: P22748
• Protein name: Carbonic anhydrase 4 (EC 4.2.1.1) (Carbonate dehydratase IV) (Carbonic anhydrase IV) (CA-IV)
• Protein function: Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH (PubMed:15563508, PubMed:16686544, PubMed:16807956, PubMed:17127057, PubMed:17314045, PubMe
• PDB: 1ZNC, 3F7B, 3F7U, 3FW3, 5IPZ, 5JN8, 5JN9, 5JNA, 5JNC, 5KU6
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00194	Carb_anhydrase	22 → 284	Eukaryotic-type carbonic anhydrase	Domain

• Tissue specificity: TISSUE SPECIFICITY: Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels. {ECO:0000269|PubMed:15563508}.
• Sequence:

  MRMLLALLALSAARPSASAESHWCYEVQAESSNYPCLVPVKWGGNCQKDRQSPINIVTTK
  AKVDKKLGRFFFSGYDKKQTWTVQNNGHSVMMLLENKASISGGGLPAPYQAKQLHLHWSD
  LPYKGSEHSLDGEHFAMEMHIVHEKEKGTSRNVKEAQDPEDEIAVLAFLVEAGTQVNEGF
  QPLVEALSNIPKPEMSTTMAESSLLDLLPKEEKLRHYFRYLGSLTTPTCDEKVVWTVFRE
  PIQLHREQILAFSQKLYYDKEQTVSMKDNVRPLQQLGQRTVIKSGAPGRPLPWALPALLG
  PMLACLLAGFLR

• Sequence length: 312

Pathways

KEGG:

Nitrogen metabolism
Metabolic pathways
Proximal tubule bicarbonate reclamation

Reactome:

Erythrocytes take up carbon dioxide and release oxygen
Erythrocytes take up oxygen and release carbon dioxide
Reversible hydration of carbon dioxide

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
Retinal dystrophy	Likely pathogenic	rs767868852, rs2544528483	RCV003889845 RCV003889849	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
CA4-related disorder	Likely benign; Conflicting classifications of pathogenicity; Uncertain significance; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cholangiocarcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Clear cell carcinoma of kidney	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Lung cancer	Benign; Likely benign; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of esophagus	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Nonpapillary renal cell carcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Retinitis pigmentosa	Benign; Likely benign; Conflicting classifications of pathogenicity; Uncertain significance	ClinVar Disgenet, Orphanet Disgenet, Orphanet Disgenet, Orphanet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
RETINITIS PIGMENTOSA 1	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Retinitis pigmentosa 17	Conflicting classifications of pathogenicity; Uncertain significance	ClinVar Disgenet, Orphanet Disgenet, Orphanet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa, Dominant	Likely benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thymoma	Benign; Likely 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 carcinosarcoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Alzheimer Disease	Alzheimer disease	Pubtator	24731980, 30541599	Associate	★☆☆☆☆ Found in Text Mining only
Autoimmune Pancreatitis	Autoimmune pancreatitis	Pubtator	15647194	Associate	★☆☆☆☆ Found in Text Mining only
Behcet Syndrome	Behcet Syndrome	BEFREE	18344446		★☆☆☆☆ Found in Text Mining only
Brain Neoplasms	Brain Neoplasms	BEFREE	31106146		★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	31182966	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	33221754	Associate	★☆☆☆☆ Found in Text Mining only
Cataract	Cataract	HPO_DG			★☆☆☆☆ Found in Text Mining only
Cholangiocarcinoma	Cholangiocarcinoma	Pubtator	33737613	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Colon Carcinoma	Colon Carcinoma	BEFREE	26071132		★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	BEFREE	26071132		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	26071132	Inhibit	★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	37804699	Associate	★☆☆☆☆ Found in Text Mining only
Conductive hearing loss	Hearing Loss	HPO_DG			★☆☆☆☆ Found in Text Mining only
Congenital hypoplasia of penis	Congenital Hypoplasia Of Penis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Conventional (Clear Cell) Renal Cell Carcinoma	Renal Carcinoma	BEFREE	9495349		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	HPO_DG			★☆☆☆☆ Found in Text Mining only
Disorder of eye	Disorder Of Eye	GENOMICS_ENGLAND_DG	15090652		★☆☆☆☆ Found in Text Mining only
Endometriosis	Endometriosis	Pubtator	38456992	Associate	★☆☆☆☆ Found in Text Mining only
Glaucoma	Glaucoma	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hodgkin Disease	Hodgkin disease	Pubtator	6370286	Associate	★☆☆☆☆ Found in Text Mining only
Hyperinsulinism	Hyperinsulinism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypogonadism	Hypogonadism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Idiopathic Pulmonary Fibrosis	Idiopathic pulmonary fibrosis	Pubtator	39289672	Associate	★☆☆☆☆ Found in Text Mining only
Intellectual Disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Keratoconus	Keratoconus	HPO_DG			★☆☆☆☆ Found in Text Mining only
Malignant tumor of colon	Colonic Neoplasms	BEFREE	26071132		★☆☆☆☆ Found in Text Mining only
Myocarditis	Myocarditis	BEFREE	16924471		★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	31106146		★☆☆☆☆ Found in Text Mining only
Non-Small Cell Lung Carcinoma	Lung carcinoma	BEFREE	29085519		★☆☆☆☆ Found in Text Mining only
Nyctalopia	Nyctalopia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Nystagmus	Nystagmus	HPO_DG			★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	HPO_DG			★☆☆☆☆ Found in Text Mining only
Optic Atrophy	Optic Atrophy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Renal Cell Carcinoma	Renal Carcinoma	BEFREE	9495349		★☆☆☆☆ Found in Text Mining only
Retinitis Pigmentosa	Retinitis Pigmentosa	BEFREE	10521250, 15090652, 15295099, 17652713, 19211803, 20450258, 9385361		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa	Retinitis Pigmentosa	LHGDN	15090652, 17652713		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa	Retinitis Pigmentosa	GENOMICS_ENGLAND_DG	15090652		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa	Retinitis Pigmentosa	CLINVAR_DG	15090652, 15563508		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis pigmentosa	Retinitis Pigmentosa	Orphanet			★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa	Retinitis pigmentosa	Pubtator	23559859	Associate	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa 17	Retinitis Pigmentosa	BEFREE	10783262, 15295099, 19211803, 20626030		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa 17	Retinitis Pigmentosa	GENOMICS_ENGLAND_DG	15090652		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa 17	Retinitis Pigmentosa	UNIPROT_DG	15563508, 17652713, 20450258		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa 17	Retinitis Pigmentosa	CTD_human_DG			★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Retinitis Pigmentosa 17	Retinitis Pigmentosa	CLINVAR_DG			★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Rod-Cone Dystrophy	Rod-cone dystrophy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Sensorineural Hearing Loss (disorder)	Hearing Loss	HPO_DG			★☆☆☆☆ Found in Text Mining only
Sjogren's Syndrome	Sjogren syndrome	Pubtator	15647194	Associate	★☆☆☆☆ Found in Text Mining only