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 OMIM: 607027

This gene encodes a catalytic subunit of vacuolar H+-ATPase (V-ATPase), which acidifies intracellular organelles and maintains cellular pH homeostasis essential for protein sorting, endocytosis, and synaptic vesicle function. Mutations cause autosomal recessive cutis laxa type IID and developmental and epileptic encephalopathy 93, with both autosomal recessive and dominant inheritance patterns reported. The pathogenic mechanism involves disruption of organellar acidification, which impairs intracellular iron homeostasis and may affect neurite development and synaptic connectivity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

GOFmechanismAR/ADLOEUF 0.362 OMIM phenotypes

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

26 unique Pathogenic / Likely Pathogenic· 222 VUS of 457 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

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?

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?

LoF OE?0.18 (0.10–0.36)

0≤0.351.4

Missense OE?0.49 (0.44–0.56)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP6V1A-related cutis laxaOTHERAR

definitiveATP6V1A-related epileptic encephalopathy, infantile or early childhoodOTHERAD

This gene — mechanism propensity

0.4685th %ile

GOF

0.3788th %ile

LOF

0.59top 25%

The Badonyi & Marsh model scores loss-of-function highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.

GOF1 literature citation · 100% of P/LP are missense

Literature Evidence

GOFThese data demonstrate gain of function for p.Asp349Asn characterized by an increased proton pumping in intracellular organelles, and loss of function for p.Asp100Tyr with decreased expression of ATP6V1A and reduced levels of lysosomal markers.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29668857 ↗

ClinVar Variant Classifications

457 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic13

VUS222

Likely Benign163

Benign22

Conflicting4

Pathogenic

Likely Pathogenic

222

VUS

163

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	13	0	0	13
Likely Pathogenic	0	13	0	0	13
VUS	16	193	9	4	222
Likely Benign	0	1	70	92	163
Benign	0	1	18	3	22
Conflicting	—				4
Total	16	221	97	99	437

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap ATP6V1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →