ATP6V1A

Chr 3ARAD

ATPase H+ transporting V1 subunit A

Also known as: ARCL2D, ATP6A1, ATP6V1A1, DEE93, HO68, IECEE3, VA68, VPP2

NCBI Gene: 523 ENSG00000114573 UniProt: P38606

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cutis laxa, autosomal recessive, type IIDMIM #617403

Developmental and epileptic encephalopathy 93MIM #618012

465

ClinVar variants

Pathogenic / LP

0.87

pLI score

Active trials

Clinical Summary— ATP6V1A

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Gene-Disease Validity (ClinGen)

autosomal recessive cutis laxa type 2D · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

55 Pathogenic / Likely Pathogenic· 221 VUS of 465 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

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.

0.36LOEUF

pLI 0.868

Z-score 4.36

OE 0.18 (0.10–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

3.37Z-score

OE missense 0.49 (0.44–0.56)

174 obs / 352.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

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.0.18 (0.10–0.36)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.44–0.56)

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.0.97

0≤1.21.6

LoF obs/exp: 6 / 33.0Missense obs/exp: 174 / 352.1Syn Z: 0.21