ATP6V0A2

Chr 12AR

ATPase H+ transporting V0 subunit a2

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

NCBI Gene: 23545ENSG00000185344UniProt: Q9Y487

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]

Primary Disease Associations & Inheritance

Cutis laxa, autosomal recessive, type IIAMIM #219200
AR
Wrinkly skin syndromeMIM #278250
AR
675
ClinVar variants
79
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ATP6V0A2
🧬
Gene-Disease Validity (ClinGen)
autosomal recessive cutis laxa type 2A · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
79 Pathogenic / Likely Pathogenic· 273 VUS of 675 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.
0.75LOEUF
pLI 0.000
Z-score 2.94
OE 0.54 (0.39–0.75)
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.
0.95Z-score
OE missense 0.88 (0.81–0.95)
412 obs / 469.6 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.0.54 (0.39–0.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.81–0.95)
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.1.02
0≤1.21.6
LoF obs/exp: 25 / 46.7Missense obs/exp: 412 / 469.6Syn Z: -0.20

ClinVar Variant Classifications

675 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic27
VUS273
Likely Benign232
Benign67
Conflicting24
52
Pathogenic
27
Likely Pathogenic
273
VUS
232
Likely Benign
67
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
0
36
0
52
Likely Pathogenic
17
1
9
0
27
VUS
2
218
46
7
273
Likely Benign
0
3
124
105
232
Benign
0
4
57
6
67
Conflicting
—24
Total35226272118675

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

View in ClinVar →

Protein Context — Lollipop Plot

ATP6V0A2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ATP6V0A2-related wrinkly skin syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cutis laxa, autosomal recessive, type IIA

MIM #219200

Molecular basis of disorder known

Autosomal recessive

Wrinkly skin syndrome

MIM #278250

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ATP6V0A2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa.
Zhang Y et al.·Mol Biol Rep
2024
ATP6V0A2-related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype.
Beyens A et al.·Exp Dermatol
2019Cohort
Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.
Zaman Q et al.·J Gene Med
2023
Metabolic cutis laxa syndromes.
Mohamed M et al.·J Inherit Metab Dis
2011Review
[Analysis of clinical features and genetic variants in a child with autosomal recessive cutis laxa due to variants of ATP6V0A2 gene].
Zhu R et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2022Case report
Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis.
Beyens A et al.·Adv Exp Med Biol
2021Review
Vacuolar H+-ATPase meets glycosylation in patients with cutis laxa.
Guillard M et al.·Biochim Biophys Acta
2009Review
Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up.
Bogdańska A et al.·Orphanet J Rare Dis
2021Natural history
A novel deletion mutation in the ATP6V0A2 gene in an Iranian patient affected by autosomal recessive cutis laxa.
Shafagh Shishavan N et al.·Ir J Med Sci
2023Case report
Review of clinical and molecular variability in autosomal recessive cutis laxa 2A.
Morlino S et al.·Am J Med Genet A
2021Review
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