CA4

Chr 17

carbonic anhydrase 4

Also known as: CAIV, Car4, RP17

NCBI Gene: 762ENSG00000167434UniProt: P22748

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtRetinitis pigmentosa 17
1
Active trials
34
Pathogenic / LP
373
ClinVar variants
8
Pubs (1 yr)
-0.1
Missense Z
1.15
LOEUF
Clinical Summary— CA4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
34 Pathogenic / Likely Pathogenic· 189 VUS of 373 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — CA4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.15LOEUF
pLI 0.000
Z-score 1.15
OE 0.68 (0.42–1.15)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.12Z-score
OE missense 1.03 (0.91–1.16)
179 obs / 174.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.68 (0.42–1.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.91–1.16)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.21
0≤1.21.6
LoF obs/exp: 10 / 14.8Missense obs/exp: 179 / 174.5Syn Z: -1.50

ClinVar Variant Classifications

373 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic14
VUS189
Likely Benign122
Benign11
Conflicting17
20
Pathogenic
14
Likely Pathogenic
189
VUS
122
Likely Benign
11
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
8
1
5
0
14
VUS
3
161
21
4
189
Likely Benign
0
7
51
64
122
Benign
0
1
6
4
11
Conflicting
—17
Total1117010372373

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CA4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CA4-related retinitis pigmentosa

limited
ADUndeterminedUncertain
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas.
Wang P et al.·Neuron
2025
Review of Cytotoxic CA4 Analogues that Do Not Target Microtubules: Implications for CA4 Development.
Tarade D et al.·Mini Rev Med Chem
2017Review
Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity.
He B et al.·EMBO Mol Med
2025
Combretastatin A4 phosphate.
West CM et al.·Anticancer Drugs
2004Review
Air pollution is the risk factor for psychiatric disorders: a two-step Mendelian randomization study.
Zhou J et al.·J Affect Disord
2025
Structural and functional alterations of the hippocampal subfields in T2DM with mild cognitive impairment and insulin resistance: A prospective study.
Yang C et al.·J Diabetes
2024Functional
Exome sequencing of a Portuguese cohort of early-onset Alzheimer's disease implicates the X-linked lysosomal gene GLA.
Tábuas-Pereira M et al.·Sci Rep
2025Cohort
Advances in MRI-based diagnosis of temporal lobe epilepsy: Correlating hippocampal subfield volumes with histopathology.
Ellsay AC et al.·J Neuroimaging
2024Review
Dusp8 affects hippocampal size and behavior in mice and humans.
Baumann P et al.·Sci Rep
2019
Hippocampal subfield morphology in regular hemodialysis patients.
Chen HJ et al.·Nephrol Dial Transplant
2023Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A viral SAVED protein with ring nuclease activity degrades the CRISPR second messenger cA4.
Orzechowski M et al.·Biochem J
2025Open Access
Novel inducible nitric oxide synthase-inhibiting cytochalasins from an oyster-derived fungus Westerdykella dispersa Ca4-13: structural insights and molecular docking analysis.
Huang SJ et al.·Bot Stud
2025Open Access
Protective Effect of α-Carbonic Anhydrase CAH3 Against Photoinhibition and Thermal Inactivation of Photosystem II in Membrane Preparations as Compared with α-Carbonic Anhydrase CA4.
Terentyev VV et al.·Biochemistry (Mosc)
2025
Assessment of CA4+ Impact on Mechanical Properties of Articular Cartilage.
Berni M et al.·Materials (Basel)
2025Open Access
Molecular basis for cA6 synthesis by a type III-A CRISPR-Cas enzyme and its conversion to cA4 production.
Goswami HN et al.·Nucleic Acids Res
2024Open Access
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Co-administration of combretastatin A4 nanoparticles and anti-PD-L1 for synergistic therapy of hepatocellular carcinoma
Zhao B et al.·J Nanobiotechnology
2021
Dual Drug Loaded, pH-Sensitive Metal-Organic Particles for Synergistic Cancer Therapy
Wu S et al.·Front Bioeng Biotechnol
2022
Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson's Disorder
Kumar S et al.·ACS Omega
2023
Enhancing anti-angiogenic immunotherapy for melanoma through injectable metal-organic framework hydrogel co-delivery of combretastatin A4 and poly(I:C)
Xiao X et al.·Nanoscale Adv
2024
Novel Genes and Genetic Loci Associated With Root Morphological Traits, Phosphorus-Acquisition Efficiency and Phosphorus-Use Efficiency in Chickpea
Thudi M et al.·Front Plant Sci
2021
Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study
Schmitt A et al.·Cells
2022
Achieving an Improved NIR Performance of Ca4-xSc2xZr1-xGe3O12:Cr3+ via [Sc3+-Sc3+] [Ca2+-Zr4+].
Chen Y et al.·Inorg Chem
2024
Enhanced anti-PD-1 therapy in hepatocellular carcinoma by tumor vascular disruption and normalization dependent on combretastatin A4 nanoparticles and DC101
Bao X et al.·Theranostics
2021
Top 8 full-text resultsSearch PubTator3 ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients