CA9

Chr 9

carbonic anhydrase 9

Also known as: CAIX, MN

NCBI Gene: 768ENSG00000107159UniProt: Q16790

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. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]

167
ClinVar variants
73
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— CA9
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
73 Pathogenic / Likely Pathogenic· 78 VUS of 167 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
1.09LOEUF
pLI 0.000
Z-score 1.21
OE 0.73 (0.50–1.09)
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.
0.11Z-score
OE missense 0.98 (0.89–1.09)
258 obs / 263.0 exp
Tolerant

Mild missense constraint

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.0.73 (0.50–1.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.89–1.09)
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.0.95
0≤1.21.6
LoF obs/exp: 17 / 23.3Missense obs/exp: 258 / 263.0Syn Z: 0.40

ClinVar Variant Classifications

167 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic9
VUS78
Likely Benign11
Benign1
64
Pathogenic
9
Likely Pathogenic
78
VUS
11
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
64
0
64
Likely Pathogenic
0
0
9
0
9
VUS
0
71
7
0
78
Likely Benign
0
11
0
0
11
Benign
0
0
0
1
1
Total082801163

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

View in ClinVar →

Protein Context — Lollipop Plot

CA9 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clear Cell Renal Cell Carcinoma: A Comprehensive Review of its Histopathology, Genetics, and Differential Diagnosis.
Nezami BG et al.·Int J Surg Pathol
2025Review
Bioactive components of Jiedu Sangen decoction against colorectal cancer: A novel and comprehensive research strategy for natural drug development.
Zheng X et al.·Phytomedicine
2025
Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.
Ni J et al.·Pharmacol Res
2024
Targeting CA9 restricts pancreatic cancer progression through pH regulation and ROS production.
Yang J et al.·Cell Oncol (Dordr)
2024
Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists.
Mohanty SK et al.·Virchows Arch
2024
NDRG1 alleviates Erastin-induced ferroptosis of hepatocellular carcinoma.
Li L et al.·BMC Cancer
2025
Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma-like carcinoma of the renal pelvis.
Fan B et al.·Mol Oncol
2022
Unveiling the hidden AP-1: revealing the crucial role of AP-1 in ccRCC at single-cell resolution.
Zheng J et al.·Mol Cancer
2023
Biomarkers Improving Genetic and Metastatic Disease Prediction in Paraganglioma: Insights From a Prospective Study.
Drossart T et al.·J Clin Endocrinol Metab
2025
Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma.
Fujita N et al.·Brain Tumor Pathol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
CA9+ cancer-associated fibroblasts cooperate with SPP1+ tumor-associated macrophages driving immune resistance in triple-negative breast cancer.
Ma Q et al.·Cell Mol Life Sci
2026🔓 Open Access
IRF1-activated CA9 accelerates oral squamous cell carcinoma process via regulating cell glycolysis, migration, apoptosis and ferroptosis.
Li Y et al.·Odontology
2026
JTC801 inhibited CA9 activation via HIF-1α to promotes alkaliptosis in vascular smooth muscle cells and alleviate the formation of aortic dissection.
Zhou Y et al.·J Mol Cell Cardiol
2026
Advanced Glycation End Products Promote PGE2 Production in Ca9-22 Cells via RAGE/TLR4-Mediated PKC-NF-κB Pathway.
Ono M et al.·Cells
2025🔓 Open Access
Apatinib triggers ferroptosis in gastric cancer via HDAC1/HIF1α/CA9 signaling axis.
Meng L et al.·Anticancer Drugs
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
High-Risk CancerLocally Advanced Breast Cancer

Three Fraction Radiation to Induce Immuno-Oncologic Response

ACTIVE NOT RECRUITING
NCT03978663Phase NALondon Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sStarted 2020-09-02
Neoadjuvant radiotherapy

External Resources

Links to major genomics databases and tools