ATP6V0A2

Chr 12AR

ATPase H+ transporting V0 subunit a2

Also known as: A2, ARCL, ARCL2A, ATP6A2, ATP6N1D, J6B7, RTF, STV1

NCBI Gene: 23545 ENSG00000185344 UniProt: Q9Y487 OMIM: 611716

The ATP6V0A2 protein is a subunit of the V0 complex of vacuolar ATPase (V-ATPase), which acidifies intracellular compartments and maintains cellular pH homeostasis, with roles in endosomal pH sensing, Golgi function, and iron metabolism. Mutations cause autosomal recessive cutis laxa type IIA and wrinkly skin syndrome, connective tissue disorders affecting skin elasticity and structure. This gene is not highly constrained against loss-of-function variants (pLI near zero), consistent with autosomal recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.752 OMIM phenotypes

Clinical Summary— ATP6V0A2

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Gene-Disease Validity (ClinGen)

autosomal recessive cutis laxa type 2A · 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

78 unique Pathogenic / Likely Pathogenic· 326 VUS of 867 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATP6V0A2

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?

0.75LOEUF

pLI 0.000

Z-score 2.94

OE 0.54 (0.39–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.95Z-score

OE missense 0.88 (0.81–0.95)

412 obs / 469.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.39–0.75)

0≤0.351.4

Missense OE?0.88 (0.81–0.95)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 25 / 46.7Missense obs/exp: 412 / 469.6Syn Z: -0.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATP6V0A2-related wrinkly skin syndromeLOFAR

This gene — mechanism propensity

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

0.7326th %ile

GOF

0.77top 25%

LOF

0.2190th %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

867 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic30

VUS326

Likely Benign320

Benign88

Conflicting36

Pathogenic

Likely Pathogenic

326

VUS

320

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	0	3	0	48
Likely Pathogenic	26	4	0	0	30
VUS	2	262	55	7	326
Likely Benign	0	4	165	151	320
Benign	0	4	78	6	88
Conflicting	—				36
Total	73	274	301	164	848

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ATP6V0A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →