CA4

Summary

CA4 (carbonic anhydrase 4, HGNC:1375) is a protein-coding gene on chromosome 17q23.1, encoding Carbonic anhydrase 4 (P22748). Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH.

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, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. This gene encodes a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and proximal renal tubules. Its exact function is not known; however, it may have a role in inherited renal abnormalities of bicarbonate transport.

Source: NCBI Gene 762 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinitis pigmentosa 17 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 356 total — 6 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes — 59 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000717

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1375
Approved symbol	CA4
Name	carbonic anhydrase 4
Location	17q23.1
Locus type	gene with protein product
Status	Approved
Aliases	CAIV, Car4
Ensembl gene	ENSG00000167434
Ensembl biotype	protein_coding
OMIM	114760
Entrez	762

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000300900, ENST00000585705, ENST00000586876, ENST00000587265, ENST00000590203, ENST00000591725, ENST00000904866, ENST00000904867, ENST00000904868, ENST00000904869, ENST00000904870, ENST00000904871, ENST00000957246, ENST00000957247

RefSeq mRNA: 1 — MANE Select: NM_000717 NM_000717

CCDS: CCDS11624

Canonical transcript exons

ENST00000300900 — 8 exons

Exon	Start	End
ENSE00001112954	60157690	60157788
ENSE00001112955	60157427	60157572
ENSE00002745558	60159230	60159546
ENSE00002807999	60149973	60150092
ENSE00003477864	60155314	60155367
ENSE00003563073	60158061	60158127
ENSE00003643831	60156560	60156715
ENSE00003660115	60158283	60158446

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 99.40.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1151 / max 437.2886, expressed in 376 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162040	3.4261	353
162039	0.6890	201

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.40	gold quality
rectum	UBERON:0001052	98.36	gold quality
cerebellar hemisphere	UBERON:0002245	98.33	gold quality
cerebellar cortex	UBERON:0002129	98.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.21	gold quality
right lung	UBERON:0002167	97.60	gold quality
cerebellum	UBERON:0002037	97.31	gold quality
colonic mucosa	UBERON:0000317	96.31	gold quality
paraflocculus	UBERON:0005351	96.10	gold quality
left lobe of thyroid gland	UBERON:0001120	95.88	gold quality
upper lobe of left lung	UBERON:0008952	95.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.34	gold quality
omental fat pad	UBERON:0010414	95.04	gold quality
peritoneum	UBERON:0002358	94.97	gold quality
upper lobe of lung	UBERON:0008948	94.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.85	gold quality
thyroid gland	UBERON:0002046	94.59	gold quality
cerebellar vermis	UBERON:0004720	94.26	gold quality
apex of heart	UBERON:0002098	93.49	gold quality
right lobe of thyroid gland	UBERON:0001119	93.25	gold quality
transverse colon	UBERON:0001157	92.54	gold quality
adipose tissue	UBERON:0001013	91.79	gold quality
right frontal lobe	UBERON:0002810	91.00	gold quality
lung	UBERON:0002048	90.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.36	gold quality
connective tissue	UBERON:0002384	90.31	gold quality
adult mammalian kidney	UBERON:0000082	90.22	gold quality
heart left ventricle	UBERON:0002084	90.19	gold quality
body of pancreas	UBERON:0001150	90.04	gold quality
cardiac ventricle	UBERON:0002082	89.92	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	5133.64
E-GEOD-135922	yes	3760.59
E-MTAB-8410	yes	3014.64
E-MTAB-10662	yes	632.83
E-GEOD-134144	yes	43.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting CA4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-3116	97.07	65.78	1324

Literature-anchored findings (GeneRIF, showing 25)

• binding by extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger (PMID:11994299)
• carbonic anhydrase IV binds EC4 of NBC1, and this interaction is essential for full NBC1 activity (PMID:14567693)
• mutation was found to cosegregate with the retinitis pigmentosa RP17 phenotype in two large families (PMID:15090652)
• CA inhibitors may have long-term adverse effects on vision. (PMID:15563508)
• characterized the CA IV expressed in Capan-1 cells (PMID:17409381)
• A novel mutation has been identified in CA4 that provides further evidence that impaired pH regulation may underlie photoreceptor degeneration in retinitis pigmentosa (PMID:17652713)
• No mutation was found in the coding regions and intron-exon boundaries of the genes for CA II, CA IV, CA XIV, kNCB1, NHE3, NHE8, NHRF1, NHRF2 and SLC26A6 amplified from genomic DNA of family members with pRTA. (PMID:17881426)
• CAIV p.R14W sequence variant found in one of the patients with Bothnia dystrophy phenotype is benign polymorphism in population of northern Sweden. (PMID:18344446)
• Apoptosis induced by the CA IV mutants could be prevented, at least partially, by treating the cells with dorzolamide, a CA inhibitor (PMID:19211803)
• renal injury inflicted by expression of human carbonic anhydrase IV folding mutants was markedly enhanced by haploinsufficiency of the endoplasmic reticulum cochaperone p58(IPK). (PMID:20308551)
• The results suggest that the expression level of carbonic anhydrase IV may be important to maintain retina function in retinitis pigmentosa. (PMID:20450258)
• compared the subcellular localization and post-translational processing of wild-type (WT)- and retinitis pigmentosa 17 mutant-CAIV in three cell types (PMID:20626030)
• data suggest that extracellular membrane-bound CAIV, but not cytosolic CAII, augments transport activity of MCT2 in a non-catalytic manner, possibly by facilitating a proton pathway other than His-88 (PMID:21680735)
• Two SNPs of carbonic anhydrase IV, which are responsible for amino acid changes, were found. The frequencies of these SNPs were not significantly different between the caries-free group and the group with caries (PMID:22021688)
• The generation of CA III and IV autoantibodies, antioxidant enzymes, and cytokines might influence each other. (PMID:23049597)
• membrane-associated CA IV contributes robust catalytic activity intracellularly, and this activity participates in regulating H(+) dynamics in the cytosol (PMID:23297198)
• Although CA IV has been shown to be active in mediating CO2 and HCO3 (-) transport in many important tissues like kidney and lung, and in isolated cells from brain and muscle, the gene for CA IV appears not to be essential. (PMID:24146379)
• Coexpression of CAIV with MCT1 and MCT4 resulted in a significant increase in MCT transport activity. (PMID:24338019)
• Carbonic anhydrase 4 is lost in papillary thyroid carcinoma but not thyroid nodules (PMID:24880201)
• CA4 is a novel tumour suppressor in Colorectal cancer through the inhibition of the Wnt signalling pathway by targeting the WTAP-WT1-TBL1 axis. CA4 methylation may serve as an independent biomarker for the recurrence of Colorectal cancer . (PMID:26071132)
• This study analyzed the direct interaction between CAIV and the two Monocarboxylate transporters (MCTs) chaperones basigin (CD147) and embigin (GP70). In human CD147, binding of CAIV was mediated by the negatively charged Glu-73. (PMID:30446621)
• highest susceptibility effect was noticed in the rs2274328 of carbonic anhydrase VI (AA vs CC) model (d = 0.18; 95% CI (confidence interval): -1.77, 2.13), but this effect was not significant [meta-analysis] (PMID:31895503)
• carbonic anhydrase 1 (CA1) and CA4 were identified as potential biomarkers of Colon adenocarcinoma due to their predictive roles in diagnosis and prognosis, and the results were further confirmed by a series of analyses. (PMID:32031891)
• Enhanced carbonic anhydrase expression with calcification and fibrosis in bronchial cartilage during COPD. (PMID:34954529)
• Carbonic Anhydrase 4 Serves as A Novel Prognostic Biomarker and Therapeutic Target for Non-Small Cell Lung Cancer: A Study Based on TCGA Samples. (PMID:36944625)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	ca4b	ENSDARG00000042293
danio_rerio	ca4a	ENSDARG00000043589
danio_rerio	ca4c	ENSDARG00000044512
mus_musculus	Car4	ENSMUSG00000000805
rattus_norvegicus	Car4	ENSRNOG00000002916
drosophila_melanogaster	CAH13	FBGN0033542
drosophila_melanogaster	CAH14	FBGN0034554
drosophila_melanogaster	CAH15	FBGN0034560
drosophila_melanogaster	CAH7	FBGN0037788
drosophila_melanogaster	CAH4	FBGN0039235
drosophila_melanogaster	CARPB	FBGN0052698
caenorhabditis_elegans		WBGENE00000279
caenorhabditis_elegans		WBGENE00000283
caenorhabditis_elegans	cah-6	WBGENE00000284

Paralogs (14): CA11 (ENSG00000063180), CA12 (ENSG00000074410), CA2 (ENSG00000104267), CA9 (ENSG00000107159), CA14 (ENSG00000118298), CA6 (ENSG00000131686), CA1 (ENSG00000133742), CA10 (ENSG00000154975), CA3 (ENSG00000164879), CA7 (ENSG00000168748), CA5B (ENSG00000169239), CA5A (ENSG00000174990), CA8 (ENSG00000178538), CA13 (ENSG00000185015)

Protein

Protein identifiers

Carbonic anhydrase 4 — P22748 (reviewed: P22748)

Alternative names: Carbonate dehydratase IV, Carbonic anhydrase IV

All UniProt accessions (4): P22748, K7EIH9, K7EKY5, K7ENI8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.

Subunit / interactions. Interacts with SLC4A4.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels.

Disease relevance. Retinitis pigmentosa 17 (RP17) [MIM:600852] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype.

Activity regulation. Activated by histamine, L-adrenaline, D-phenylalanine, L- and D-histidine. Inhibited by coumarins, saccharin, sulfonamide derivatives such as acetazolamide and Foscarnet (phosphonoformate trisodium salt).

Similarity. Belongs to the alpha-carbonic anhydrase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22748-1	1	yes
P22748-2	2

RefSeq proteins (1): NP_000708* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001148	CA_dom	Domain
IPR018338	Carbonic_anhydrase_a-class_CS	Conserved_site
IPR023561	Carbonic_anhydrase_a-class	Family
IPR036398	CA_dom_sf	Homologous_superfamily
IPR041874	CA4/CA15	Family

Pfam: PF00194

Enzyme classification (BRENDA):

• EC 4.2.1.1 — carbonic anhydrase (BRENDA: 178 organisms, 196 substrates, 2137 inhibitors, 263 Km, 291 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CO2	0.012–4700	194
4-NITROPHENYL ACETATE	0.0024–30.53	16
H2CO3	0.434–112.7	16
HCO3-	9.3–37	4
P-NITROPHENYL ACETATE	3.86–6.8	4
4-NITROPHENYL PHOSPHATE	0.935–2.195	2
COS	1.86	1
HISTAMINE	7.9	1
CS2	—	0

Catalyzed reactions (Rhea), 1 shown:

• hydrogencarbonate + H(+) = CO2 + H2O (RHEA:10748)

UniProt features (50 total): strand 16, helix 10, sequence variant 6, binding site 4, disulfide bond 2, splice variant 2, turn 2, signal peptide 1, chain 1, propeptide 1, mutagenesis site 1, sequence conflict 1, domain 1, active site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3FW3	X-RAY DIFFRACTION	1.72
5KU6	X-RAY DIFFRACTION	1.8
5JN8	X-RAY DIFFRACTION	1.85
3F7U	X-RAY DIFFRACTION	2
5JNA	X-RAY DIFFRACTION	2
5JNC	X-RAY DIFFRACTION	2
3F7B	X-RAY DIFFRACTION	2.05
5IPZ	X-RAY DIFFRACTION	2.1
5JN9	X-RAY DIFFRACTION	2.1
1ZNC	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22748-F1	89.86	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 88 (proton donor/acceptor)

Ligand- & substrate-binding residues (4): 115; 117; 140; 225–226

Post-translational modifications (1): 284

Disulfide bonds (2): 24–36, 46–229

Mutagenesis-validated functional residues (1):

Position	Phenotype
284	loss of c-terminal domain removal and abolishes carbonate dehydratase activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1237044	Erythrocytes take up carbon dioxide and release oxygen
R-HSA-1247673	Erythrocytes take up oxygen and release carbon dioxide
R-HSA-1475029	Reversible hydration of carbon dioxide
R-HSA-1430728	Metabolism
R-HSA-1480926	O2/CO2 exchange in erythrocytes
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 246 (showing top): GOMF_CARBONATE_DEHYDRATASE_ACTIVITY, NKX25_02, GOCC_SECRETORY_GRANULE, MODULE_45, GOCC_CELL_SURFACE, MARTINEZ_RB1_TARGETS_UP, GOCC_TRANS_GOLGI_NETWORK, DELYS_THYROID_CANCER_DN, RYTAAWNNNTGAY_UNKNOWN, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, HP1SITEFACTOR_Q6, SANSOM_APC_TARGETS_DN, MODULE_88, GOCC_APICAL_PLASMA_MEMBRANE

GO Biological Process (1): bicarbonate transport (GO:0015701)

GO Molecular Function (5): carbonate dehydratase activity (GO:0004089), zinc ion binding (GO:0008270), protein binding (GO:0005515), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (15): rough endoplasmic reticulum (GO:0005791), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), brush border membrane (GO:0031526), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
O2/CO2 exchange in erythrocytes	2
Metabolism	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
intracellular membrane-bounded organelle	2
membrane	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
transport	1
hydro-lyase activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
endoplasmic reticulum	1
endomembrane system	1
Golgi apparatus subcompartment	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
apical part of cell	1
plasma membrane region	1
transport vesicle	1
secretory granule	1
brush border	1
apical plasma membrane	1
cell projection membrane	1
extracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

2170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CA4	CA3	P07451	822
CA4	CYP24A1	Q07973	762
CA4	SLC4A4	Q9Y6R1	747
CA4	PKD2L1	Q9P0L9	723
CA4	FSCN2	O14926	719
CA4	PRSS12	P56730	713
CA4	RP9	Q8TA86	710
CA4	PRPF31	Q8WWY3	686
CA4	TALDO1	P37837	680
CA4	PRPF3	O43395	668
CA4	IMPDH1	P20839	667
CA4	PRPF8	Q6P2Q9	653
CA4	CERKL	Q49MI3	640
CA4	TOPORS	Q9NS56	640
CA4	PDE6G	P18545	639

IntAct

11 interactions, top by confidence:

A	B	Type	Score
CA4	SLC4A4	psi-mi:“MI:0403”(colocalization)	0.460
CA4	SLC4A4	psi-mi:“MI:0915”(physical association)	0.460
CA4	CDK18	psi-mi:“MI:0915”(physical association)	0.400
CA4	ALDH1A2	psi-mi:“MI:0915”(physical association)	0.400
CA4	PRDX2	psi-mi:“MI:0915”(physical association)	0.370
CA4	PIH1D1	psi-mi:“MI:0915”(physical association)	0.370
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
CA4	CDK6	psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): WTAP (Affinity Capture-MS), WTAP (Affinity Capture-Western), CA4 (Affinity Capture-Western), CDK18 (Affinity Capture-MS), CA4 (Affinity Capture-MS), CA4 (Co-fractionation), CA4 (Reconstituted Complex), CDK18 (Affinity Capture-MS), CDK6 (Affinity Capture-MS), ALDH1A2 (Affinity Capture-MS), CA4 (Negative Genetic), CA4 (Positive Genetic), CA4 (Affinity Capture-MS), PRDX2 (Two-hybrid), PIH1D1 (Two-hybrid)

ESM2 similar proteins: A0JN41, A2VE04, F4HUC4, F4IHR4, F4JIK2, O04846, O43570, O70354, O75493, P08060, P09172, P0DO50, P15101, P18761, P18915, P22748, P23280, P28651, P35219, P48283, P48284, P61215, Q05754, Q10462, Q18932, Q5PPN4, Q5R4U0, Q5R665, Q5TZ24, Q64237, Q64444, Q68CI2, Q6UVY6, Q6ZNA5, Q75N35, Q7TT41, Q865C0, Q866X6, Q866X7, Q8CI85

Diamond homologs: A0ZSF2, A0ZSF3, A0ZSF4, A0ZSF5, A0ZSF6, A0ZSF7, B3A0P2, B3A0Q6, B8V7P3, F4HUC4, O43570, P08060, P18761, P22748, P23280, P23471, P23589, P35218, P43165, P48284, P83299, P84537, Q10462, Q16790, Q27504, Q27908, Q62656, Q84UV8, Q865C0, Q8CI85, Q8UWA5, Q8VHB5, Q92051, Q9ERQ8, Q9FM99, Q9MZ30, Q9NL38, Q9QZA0, Q9Y2D0, P07630

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

356 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	10
Uncertain significance	186
Likely benign	114
Benign	11

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1444632	NC_000017.10:g.(?58230965)(58235066_?)del	Pathogenic
1455150	NC_000017.10:g.(?58227396)(58236785_?)del	Pathogenic
1519203	NM_000717.5(CA4):c.102C>A (p.Tyr34Ter)	Pathogenic
2095265	NM_000717.5(CA4):c.58G>T (p.Glu20Ter)	Pathogenic
3689423	NM_000717.5(CA4):c.138C>A (p.Cys46Ter)	Pathogenic
3699233	NM_000717.5(CA4):c.250C>T (p.Gln84Ter)	Pathogenic
1024689	NM_000717.5(CA4):c.656G>A (p.Arg219His)	Likely pathogenic
1360011	NM_000717.5(CA4):c.415-2_416del	Likely pathogenic
1479585	NM_000717.5(CA4):c.112+1G>A	Likely pathogenic
1910917	NM_000717.5(CA4):c.113-2A>C	Likely pathogenic
2056863	NM_000717.5(CA4):c.268+1G>A	Likely pathogenic
2127685	NM_000717.5(CA4):c.415-1G>A	Likely pathogenic
2193862	NM_000717.5(CA4):c.513+1G>T	Likely pathogenic
3028475	NM_000717.5(CA4):c.687C>A (p.Cys229Ter)	Likely pathogenic
3028479	NM_000717.5(CA4):c.937T>C (p.Ter313Arg)	Likely pathogenic
808304	NM_000717.5(CA4):c.368del (p.Tyr123fs)	Likely pathogenic

SpliceAI

1484 predictions. Top by Δscore:

Variant	Effect	Δscore
17:60150092:GG:G	donor_loss	1.0000
17:60150093:GTGAG:G	donor_loss	1.0000
17:60156553:T:TA	acceptor_gain	1.0000
17:60156558:A:AG	acceptor_gain	1.0000
17:60156558:AGT:A	acceptor_gain	1.0000
17:60156559:G:GT	acceptor_gain	1.0000
17:60156559:GT:G	acceptor_gain	1.0000
17:60156559:GTG:G	acceptor_gain	1.0000
17:60156559:GTGC:G	acceptor_gain	1.0000
17:60156559:GTGCC:G	acceptor_gain	1.0000
17:60156674:A:G	donor_gain	1.0000
17:60156678:G:GT	donor_gain	1.0000
17:60157571:AGGTG:A	donor_loss	1.0000
17:60157572:GGTG:G	donor_loss	1.0000
17:60157573:G:C	donor_loss	1.0000
17:60157574:T:G	donor_loss	1.0000
17:60157679:A:AG	acceptor_gain	1.0000
17:60157786:G:GT	donor_gain	1.0000
17:60158057:CCAG:C	acceptor_loss	1.0000
17:60158058:CAGGC:C	acceptor_loss	1.0000
17:60158059:A:AG	acceptor_gain	1.0000
17:60158059:A:T	acceptor_loss	1.0000
17:60158059:AG:A	acceptor_gain	1.0000
17:60158059:AGGCT:A	acceptor_gain	1.0000
17:60158060:G:GG	acceptor_gain	1.0000
17:60158060:GG:G	acceptor_gain	1.0000
17:60158060:GGCT:G	acceptor_gain	1.0000
17:60158060:GGCTG:G	acceptor_gain	1.0000
17:60158123:ACCTG:A	donor_gain	1.0000
17:60158124:CCTG:C	donor_gain	1.0000

AlphaMissense

2026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:60156573:G:C	W42C	0.996
17:60156573:G:T	W42C	0.996
17:60159297:G:C	R271T	0.995
17:60157507:C:G	H117D	0.994
17:60157512:G:C	W118C	0.994
17:60157512:G:T	W118C	0.994
17:60157510:T:A	W118R	0.993
17:60157510:T:C	W118R	0.993
17:60159297:G:T	R271M	0.993
17:60159298:G:C	R271S	0.993
17:60159298:G:T	R271S	0.993
17:60158358:G:C	R219P	0.992
17:60158405:T:A	W235R	0.992
17:60158405:T:C	W235R	0.992
17:60157538:A:T	E127V	0.991
17:60158387:T:A	C229S	0.991
17:60158388:G:C	C229S	0.991
17:60156571:T:A	W42R	0.990
17:60156571:T:C	W42R	0.990
17:60158407:G:C	W235C	0.990
17:60158407:G:T	W235C	0.990
17:60156605:C:A	P53H	0.989
17:60156702:T:A	N85K	0.989
17:60156702:T:G	N85K	0.989
17:60157539:G:C	E127D	0.989
17:60157539:G:T	E127D	0.989
17:60158388:G:A	C229Y	0.989
17:60157542:C:A	H128Q	0.988
17:60157542:C:G	H128Q	0.988
17:60155324:G:C	W23C	0.987

dbSNP variants (sampled 300 via entrez): RS1000002338 (17:60158711 G>A), RS1000123915 (17:60151630 G>A), RS1000174934 (17:60150940 T>C,G), RS1000264808 (17:60164405 C>G,T), RS1000271030 (17:60154264 G>A), RS1000346940 (17:60149207 T>C), RS1000530241 (17:60164795 C>T), RS1000553150 (17:60155107 C>T), RS1000580621 (17:60154492 C>A,T), RS1000619858 (17:60153839 G>A), RS1000661685 (17:60159409 C>T), RS1000770498 (17:60149786 A>C,G), RS1000823429 (17:60149693 G>A), RS1000904816 (17:60155421 A>G), RS1001177048 (17:60162361 C>T)

Disease associations

OMIM: gene MIM:114760 | disease phenotypes: MIM:268000, MIM:600852

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 17	Strong	Autosomal dominant
retinitis pigmentosa	Supportive	Autosomal dominant

Mondo (3): retinitis pigmentosa (MONDO:0019200), retinitis pigmentosa 17 (MONDO:0010945), inherited retinal dystrophy (MONDO:0019118)

Orphanet (2): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss
HP:0008046	Abnormal retinal vascular morphology
HP:0011505	Cystoid macular edema
HP:0012426	Optic disc drusen
HP:0030466	Abnormal full-field electroretinogram
HP:0030488	Abnormal central response of multifocal electroretinogram
HP:0030610	Photoreceptor outer segment loss on macular OCT

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C563437	Retinitis Pigmentosa 17 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2095180 (PROTEIN FAMILY), CHEMBL3729 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

59 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,095,163 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL19	METHAZOLAMIDE	4	65
CHEMBL20	ACETAZOLAMIDE	4	28,768
CHEMBL750	ZONISAMIDE	4	16,649
CHEMBL1054	TRICHLORMETHIAZIDE	4	11,619
CHEMBL1055	CHLORTHALIDONE	4	20,442
CHEMBL1060	SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	305,151
CHEMBL112	ACETAMINOPHEN	4	157,242
CHEMBL1141	POTASSIUM IODIDE	4	164,544
CHEMBL118	CELECOXIB	4	112,844
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200731	POTASSIUM CHLORIDE	4	396,239
CHEMBL1286	LEVETIRACETAM	4	13,997
CHEMBL1355	SODIUM CITRATE	4	550,390
CHEMBL1356	SODIUM BENZOATE	4	244,527
CHEMBL14060	PHENOL	4	1,871,332
CHEMBL17	DICHLORPHENAMIDE	4	9,022
CHEMBL18	ETHOXZOLAMIDE	4	3,042
CHEMBL21	SULFANILAMIDE	4	153,075
CHEMBL2105581	VERALIPRIDE	4	1,165
CHEMBL218490	DORZOLAMIDE	4	10,216
CHEMBL220491	BRINZOLAMIDE	4
CHEMBL220492	TOPIRAMATE	4
CHEMBL255863	NILOTINIB	4
CHEMBL325041	BORTEZOMIB	4
CHEMBL35	FUROSEMIDE	4
CHEMBL406	INDAPAMIDE	4
CHEMBL419	MAFENIDE	4
CHEMBL424	SALICYLIC ACID	4
CHEMBL537	HYDROQUINONE	4
CHEMBL58323	LACOSAMIDE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Carbonic anhydrases

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
methazolamide	Inhibition	7.62	pKi
acetazolamide	Inhibition	7.6	pKi
topiramate	Inhibition	7.37	pKi
salvianolic acid A	Inhibition	7.17	pKi
chlorthalidone	Inhibition	6.71	pKi
compound 5b [PMID: 31287314]	Inhibition	6.03	pKi
compound 5a [PMID: 31287314]	Inhibition	5.0	pKi
diclofenamide	Inhibition	4.82	pKi

Binding affinities (BindingDB)

63 measured of 92 human assays (130 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid	EC50	0.0469 nM
2-(3-hydroxyphenyl)-1,1-dioxo-3-[(prop-2-yn-1-ylamino)methyl]-2H-1,7,2-thieno[3,2-e][1,2]thiazine-6-sulfonamide hydrochloride	IC50	0.6 nM
Compound 17g1	IC50	0.79 nM
Compound 5b	IC50	0.82 nM
3-(morpholin-4-ylmethyl)-1,1-dioxo-2-(prop-2-en-1-yl)-2H-1,7,2-thieno[3,2-e][1,2]thiazine-6-sulfonamide	IC50	0.99 nM
Compound 17m1	IC50	1.05 nM
Compound 17a7	IC50	1.11 nM
2-(3-hydroxyphenyl)-3-(morpholin-4-ylmethyl)-1,1-dioxo-2H-1,7,2-thieno[3,2-e][1,2]thiazine-6-sulfonamide	IC50	1.15 nM
2-(3-Methoxyphenyl)-3-[(4-morpholinyl)methyl]-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide	IC50	1.27 nM
Compound 17n1	IC50	1.5 nM
2-methyl-3-(morpholin-4-ylmethyl)-1,1-dioxo-2H-1,7,2-thieno[3,2-e][1,2]thiazine-6-sulfonamide hydrochloride	IC50	1.66 nM
Compound 17j1	IC50	2.01 nM
2-[2-(Propylamino)ethyl]-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide hydrochloride	IC50	2.25 nM
Compound 17i1	IC50	2.63 nM
aliphatic sulfamate, 1	KI	3.7 nM
5-{[(4-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazole-2-sulfonamide	IC50	3.9 nM
Compound 17h1	IC50	5.58 nM
EZA4	KI	25 nM
N-(3-morpholinopropyl)benzene-1,4-disulfonamide (I-2)	IC50	57.7 nM
N-(4-diethylaminoethoxybenzyl)benzene-1,4-bis-sulfonamide (I-3)	IC50	59.8 nM
2-(hydrazinecarbonyl)-3-(2-methylphenyl)-1H-indole-5-sulfonamide	KI	107 nM
3-(2-bromophenyl)-2-(hydrazinecarbonyl)-1H-indole-5-sulfonamide	KI	110 nM
4-Sulfamoyl-N-(3-morpholinopropyl)benzamide (I-1)	IC50	231 nM
Topiramate, 3	KI	250 nM
6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c]chromen-3-yl sulfamate	IC50	300 nM
JFD00715	KI	328 nM
trichloromethiazide, 6	KI	345 nM
DCP5	KI	350 nM
bis-sulfamate, 3	KI	378 nM
aliphatic sulfamate, 2	KI	530 nM
3-(2-fluorophenyl)-2-(hydrazinecarbonyl)-1H-indole-5-sulfonamide	KI	621 nM
CNO(-1)	KI	700 nM
Investigational agent, 5	KI	810 nM
Investigational agent, 4	KI	850 nM
bis-sulfamate, 4	KI	890 nM
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one	KI	2200 nM
BMCL182567 Compound 6b	KI	2840 nM
amino-N-{[(1R,2S,6S,9R)-4,4,11,11-tetramethyl-3,5,7,10,12-pentaoxatricyclo[7.3.0.0^{2,6}]dodecan-6-yl]methyl}sulfonamide	KI	3450 nM
[2-(cycloheptylmethyl)-1,1-dioxo–benzothiophen-6-yl] sulfamate	KI	3600 nM
salicylic acid	KI	9900 nM
4-chloro-N-(2-methyl-2,3-dihydro-1H-indol-1-yl)-3-sulfamoylbenzamide	KD	10000 nM
phenol	KI	10200 nM
9(R(S))-Hydroxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-2(R(S))-yl sulfate (8)	KI	32700 nM
3,5-difluorophenol	KI	38800 nM
trans-(1R(S),6R(S))-6-Hydroxycyclohex-3-enyl hydrogen sulfate (4)	KI	41300 nM
Dorzolamide, DZA	KI	50000 nM
7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide	KI	54000 nM
5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one	IC50	64300 nM
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one	IC50	72800 nM
trans-(1R(S),8R(S),Z)-8-Hydroxycyclooct-4-enyl hydrogen sulfate (6)	KI	77200 nM

ChEMBL bioactivities

1932 potent at pChembl≥5 of 2056 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Kd	0.01	nM	CHEMBL4569008
11.00	Kd	0.01	nM	CHEMBL4451500
11.00	Kd	0.01	nM	CHEMBL4584546
10.70	Kd	0.02	nM	CHEMBL4572161
10.70	Kd	0.02	nM	CHEMBL4562296
10.52	Kd	0.03	nM	CHEMBL4450545
10.52	Kd	0.03	nM	CHEMBL4173471
10.52	Kd	0.03	nM	CHEMBL4450456
10.52	Kd	0.03	nM	CHEMBL4593681
10.49	Kd	0.032	nM	CHEMBL4173471
10.40	Kd	0.04	nM	CHEMBL4166964
10.40	Kd	0.04	nM	CHEMBL4436290
10.30	Kd	0.05	nM	CHEMBL4166964
10.22	Kd	0.06	nM	CHEMBL4565224
10.22	Kd	0.06	nM	CHEMBL4468834
10.22	Kd	0.06	nM	CHEMBL4521683
10.21	Kd	0.062	nM	CHEMBL4441730
10.05	Kd	0.089	nM	CHEMBL4553790
10.05	Kd	0.09	nM	CHEMBL4165570
10.03	Kd	0.093	nM	CHEMBL4449149
10.00	Kd	0.099	nM	CHEMBL4165570
10.00	Kd	0.1	nM	CHEMBL4558235
9.96	Kd	0.11	nM	CHEMBL4456084
9.96	Kd	0.11	nM	CHEMBL4475073
9.96	Kd	0.11	nM	CHEMBL4446052
9.92	Kd	0.12	nM	CHEMBL4475315
9.89	Kd	0.13	nM	CHEMBL4452277
9.85	Kd	0.14	nM	CHEMBL4218335
9.82	Kd	0.15	nM	CHEMBL4573894
9.82	Kd	0.15	nM	CHEMBL4592616
9.80	Kd	0.16	nM	CHEMBL4576689
9.77	Kd	0.17	nM	CHEMBL4555622
9.77	Kd	0.17	nM	CHEMBL4456851
9.77	Kd	0.17	nM	CHEMBL4539233
9.77	Kd	0.17	nM	CHEMBL4468310
9.77	Kd	0.17	nM	CHEMBL4166643
9.77	Kd	0.17	nM	CHEMBL4445515
9.74	Kd	0.18	nM	CHEMBL4166643
9.74	Kd	0.18	nM	CHEMBL4458989
9.74	Kd	0.18	nM	CHEMBL4573916
9.74	Kd	0.18	nM	CHEMBL4462447
9.74	Kd	0.18	nM	CHEMBL4578934
9.72	Kd	0.19	nM	CHEMBL4516072
9.70	Ki	0.2	nM	CHEMBL4552380
9.70	Ki	0.2	nM	CHEMBL4460315
9.70	Ki	0.2	nM	CHEMBL4434661
9.70	Ki	0.2	nM	CHEMBL282157
9.66	Kd	0.22	nM	CHEMBL4560953
9.66	Kd	0.22	nM	CHEMBL4474251
9.66	Ki	0.22	nM	CHEMBL4577408

PubChem BioAssay actives

1994 with measured affinity, of 2778 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[(4-chloro-2-phenylsulfanyl-5-sulfamoylbenzoyl)amino]propyl acetate	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
methyl 4-[(2-benzylsulfanyl-4-chloro-5-sulfamoylbenzoyl)amino]butanoate	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-N-(3-hydroxypropyl)-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
2-benzylsulfanyl-4-bromo-N-butyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-bromo-N-butyl-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-bromo-N-(2-hydroxyethyl)-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
N-butyl-4-chloro-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-N-(2-methoxyethyl)-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
2,4-dichloro-N-(3-hydroxypropyl)-5-sulfamoylbenzamide	1361384: Binding affinity to recombinant human carbonic anhydrase 4 (19 to 284 residues) expressed in mammalian expression system assessed as intrinsic Kd in presence of ANS by fluorescent thermal shift assay	kd	<0.0001	uM
N-benzyl-4-chloro-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-2-cyclohexylsulfanyl-N-(2-methoxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
N-butyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
methyl 4-[(4-chloro-2-phenylsulfanyl-5-sulfamoylbenzoyl)amino]butanoate	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-chloro-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
4-[(4-chloro-2-phenylsulfanyl-5-sulfamoylbenzoyl)amino]butanoic acid	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
2,4-dichloro-N-(2-methoxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	<0.0001	uM
N-benzyl-2,4-dichloro-5-sulfamoylbenzamide	1361384: Binding affinity to recombinant human carbonic anhydrase 4 (19 to 284 residues) expressed in mammalian expression system assessed as intrinsic Kd in presence of ANS by fluorescent thermal shift assay	kd	0.0001	uM
4-bromo-N-butyl-2-cyclohexylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
2-(benzenesulfonyl)-4-chloro-N-(2-methoxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
4-bromo-N-butyl-2-(2-hydroxyethylsulfanyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
4-bromo-N-butyl-2-(2-phenylethylsulfanyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
4-chloro-2-cyclohexylsulfanyl-N-(3-hydroxypropyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
2-benzylsulfanyl-4-chloro-N-(2-hydroxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
4-chloro-N-cyclohexyl-2-phenylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
N-(benzimidazol-1-yl)-4-chloro-2-phenylsulfanyl-5-sulfamoylbenzamide	1373179: Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 4 expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay	kd	0.0001	uM
1-(2-chloro-3,5-dimethyl-4-sulfamoylphenyl)-N-[(E)-(4-methoxyphenyl)methylideneamino]-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
N-(3,5-dimethylpyrazol-1-yl)-1-(3,5-dimethyl-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
1-(2-chloro-3,5-dimethyl-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxylic acid	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
2-benzylsulfanyl-4-chloro-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0001	uM
N-[(E)-(4-bromophenyl)methylideneamino]-1-(2-chloro-3,5-dimethyl-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
1-(2-bromophenyl)-5-oxo-N-(4-sulfamoylphenyl)pyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
1-(3,5-dimethyl-4-sulfamoylphenyl)-N-[(E)-(4-methoxyphenyl)methylideneamino]-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0001	uM
2-benzylsulfanyl-4-bromo-N-(2-hydroxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
4-bromo-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
2-(benzenesulfinyl)-4-bromo-N-(2-hydroxyethyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
2-(benzenesulfonyl)-4-bromo-N-butyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
N-benzyl-4-chloro-2-cyclohexylsulfanyl-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
2,4-dibromo-N-butyl-5-sulfamoylbenzamide	1361384: Binding affinity to recombinant human carbonic anhydrase 4 (19 to 284 residues) expressed in mammalian expression system assessed as intrinsic Kd in presence of ANS by fluorescent thermal shift assay	kd	0.0002	uM
4-[1-[(2R)-1-(3-azabicyclo[3.2.2]nonan-3-yl)-3-methyl-1-oxobutan-2-yl]triazol-4-yl]benzenesulfonamide	1557414: Inhibition of carbonic anhydrase (unknown origin)	ki	0.0002	uM
4-[(2-benzylsulfanyl-4-chloro-5-sulfamoylbenzoyl)amino]butanoic acid	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
4-chloro-2-(2-phenylethylsulfanyl)-5-sulfamoylbenzamide	1520082: Binding affinity to recombinant human carbonic anhydrase 4 expressed in Escherichia coli expression system assessed as kinetic dissociation constant fluorescent thermal shift assay	kd	0.0002	uM
3-chloro-4-[4-(hydrazinecarbonyl)-2-oxopyrrolidin-1-yl]-2,6-dimethylbenzenesulfonamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM
1-(3-bromophenyl)-5-oxo-N-(4-sulfamoylphenyl)pyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM
N-[(E)-benzylideneamino]-5-oxo-1-(4-sulfamoylphenyl)pyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM
N-[(E)-benzylideneamino]-1-(3,5-dimethyl-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM
(2R)-3-phenyl-2-[4-(4-sulfamoylphenyl)triazol-1-yl]-N-(2-thiophen-3-ylethyl)propanamide	1557414: Inhibition of carbonic anhydrase (unknown origin)	ki	0.0002	uM
1-(2-chloro-3,5-dimethyl-4-sulfamoylphenyl)-N-[(E)-(4-nitrophenyl)methylideneamino]-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM
1-(3,5-dimethyl-4-sulfamoylphenyl)-N-[(E)-(4-nitrophenyl)methylideneamino]-5-oxopyrrolidine-3-carboxamide	1515317: Binding affinity to recombinant human CA4 assessed as intrinsic dissociation constant by DSF-based fluorescence thermal shift assay	kd	0.0002	uM

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression, affects expression	6
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
sulfamic acid	decreases activity	1
oryzalin	affects binding, decreases activity	1
butyraldehyde	increases expression	1
chloric acid	decreases activity	1
sodium metasilicate	decreases activity	1
potassium periodate	decreases activity	1
molybdate	decreases activity	1
tungstate	decreases activity	1
pentanal	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Norethindrone Acetate	increases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Acetazolamide	decreases activity, affects binding	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Amphotericin B	decreases expression	1

ChEMBL screening assays

202 unique, capped per target: 195 binding, 6 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3386760	Binding	Inhibition of carbonic anhydrase (unknown origin)	Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses. — Bioorg Med Chem
CHEMBL4187334	ADMET	Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 4 expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay	Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors. — Bioorg Med Chem
CHEMBL863243	Functional	Activation constant against recombinant human CA IV isozyme by the esterase method	Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

234 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa
NCT01068561	PHASE1	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa