CA8

Chr 8AR

carbonic anhydrase 8 (inactive)

Also known as: CA-RP, CA-VIII, CALS, CAMRQ3, CARP, SCAR34

NCBI Gene: 767ENSG00000178538UniProt: P35219

The protein encoded by this gene was initially named CA-related protein because of sequence similarity to other known carbonic anhydrase genes. However, the gene product lacks carbonic anhydrase activity (i.e., the reversible hydration of carbon dioxide). The gene product continues to carry a carbonic anhydrase designation based on clear sequence identity to other members of the carbonic anhydrase gene family. The absence of CA8 gene transcription in the cerebellum of the lurcher mutant in mice with a neurologic defect suggests an important role for this acatalytic form. Mutations in this gene are associated with cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CMARQ3). Polymorphisms in this gene are associated with osteoporosis, and overexpression of this gene in osteosarcoma cells suggests an oncogenic role. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Primary Disease Associations & Inheritance

Spinocerebellar ataxia, autosomal recessive 34MIM #613227
AR
130
ClinVar variants
38
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— CA8
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 36 VUS of 130 total submissions

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.
0.67LOEUF
pLI 0.008
Z-score 2.64
OE 0.36 (0.20–0.67)
Tolerant

Typical tolerance to LoF variation

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.
1.24Z-score
OE missense 0.72 (0.62–0.84)
115 obs / 159.0 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.0.36 (0.20–0.67)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.62–0.84)
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.1.01
0≤1.21.6
LoF obs/exp: 7 / 19.6Missense obs/exp: 115 / 159.0Syn Z: -0.07

ClinVar Variant Classifications

130 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic6
VUS36
Likely Benign11
Benign36
32
Pathogenic
6
Likely Pathogenic
36
VUS
11
Likely Benign
36
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
28
0
32
Likely Pathogenic
2
2
2
0
6
VUS
0
29
7
0
36
Likely Benign
0
0
2
9
11
Benign
1
1
30
4
36
Total3366913121

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

View in ClinVar →

Protein Context — Lollipop Plot

CA8 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CA8-related cerebellar ataxia, intellectual developmental disorder, and dysequilibrium syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spinocerebellar ataxia, autosomal recessive 34

MIM #613227

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.
Tolonen JP et al.·Mov Disord
2024
Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.
Kaiyrzhanov R et al.·Mov Disord
2024
Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.
Levitt RC et al.·Mol Ther
2025
Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.
Upadhyay U et al.·PLoS Genet
2019
Potential drug targets for ovarian cancer identified through Mendelian randomization and colocalization analysis.
Liu S et al.·J Ovarian Res
2025
Cerebellar ataxia with normal intellect associated with a homozygous truncating variant in CA8.
Richmond CM et al.·Clin Genet
2020Case report
Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII.
Kaya N et al.·Am J Med Genet B Neuropsychiatr Genet
2011Case report
Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.
Aspatwar A et al.·Hum Mol Genet
2013Functional
A Proteomic Landscape of Candida albicans in the Stepwise Evolution to Fluconazole Resistance.
Song N et al.·Antimicrob Agents Chemother
2022
Novel homozygous variant of carbonic anhydrase 8 gene expanding the phenotype of cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3.
Paternoster L et al.·Am J Med Genet A
2020Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools