CA5A

Chr 16AR

carbonic anhydrase 5A

Also known as: CA5, CA5AD, CAV, CAVA, GS1-21A4.1

NCBI Gene: 763 ENSG00000174990 UniProt: P35218 OMIM: 114761

The carbonic anhydrase VA protein catalyzes the reversible conversion of carbon dioxide to bicarbonate within mitochondria, providing bicarbonate for essential enzymes in the urea and Krebs cycles. Autosomal recessive mutations cause hyperammonemia due to carbonic anhydrase VA deficiency, disrupting ureagenesis and gluconeogenesis primarily in the liver. The pathogenic mechanism involves loss of function of this mitochondrial enzyme.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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 VA is localized in the mitochondria and expressed primarily in the liver. It may play an important role in ureagenesis and gluconeogenesis. CA5A gene maps to chromosome 16q24.3 and an unprocessed pseudogene has been assigned to 16p12-p11.2. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.971 OMIM phenotype

Clinical Summary— CA5A

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Gene-Disease Validity (ClinGen)

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 112 VUS of 242 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CA5A

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?

0.97LOEUF

pLI 0.000

Z-score 1.65

OE 0.56 (0.33–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.20Z-score

OE missense 1.25 (1.12–1.40)

222 obs / 177.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.56 (0.33–0.97)

0≤0.351.4

Missense OE?1.25 (1.12–1.40)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 9 / 16.2Missense obs/exp: 222 / 177.0Syn Z: -1.53

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCA5A-related hyperammonemia due to carbonic anhydrase VA deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.6247th %ile

LOF

0.2678th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

242 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic6

VUS112

Likely Benign87

Benign10

Conflicting11

Pathogenic

Likely Pathogenic

112

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	6	0	11
Likely Pathogenic	3	1	2	0	6
VUS	2	103	6	1	112
Likely Benign	0	7	27	53	87
Benign	0	2	5	3	10
Conflicting	—				11
Total	9	114	46	57	237

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 73) ClinVar copy-number / structural variants overlap CA5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →