ATP6V0A1

Chr 17ADAR

ATPase H+ transporting V0 subunit a1

Also known as: ATP6N1, ATP6N1A, DEE104, NEDEBA, Stv1, VPP1, Vph1, a1

NCBI Gene: 535 ENSG00000033627 UniProt: Q93050 OMIM: 192130

The protein is a subunit of the V0 complex of vacuolar ATPase that acidifies intracellular organelles including lysosomes, endosomes, and synaptic vesicles, which is essential for neuronal development and connectivity. Mutations cause developmental and epileptic encephalopathy and neurodevelopmental disorder with epilepsy and brain atrophy through both autosomal dominant and autosomal recessive inheritance patterns. The high constraint scores indicate the gene is highly intolerant to loss-of-function variants, suggesting mutations can cause disease through multiple mechanisms depending on the specific variant type.

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 gene encodes one of three A subunit proteins and the encoded protein is associated with clathrin-coated vesicles. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 104MIM #619970

Neurodevelopmental disorder with epilepsy and brain atrophyMIM #619971

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Developmental and epileptic encephalopathy 104; Neurodevelopmental disorder with epilepsy and brain atrophy; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.27LOEUF

pLI 0.998

Z-score 5.56

OE 0.14 (0.08–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.74Z-score

OE missense 0.52 (0.47–0.57)

246 obs / 475.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.14 (0.08–0.27)

0≤0.351.4

Missense OE?0.52 (0.47–0.57)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 7 / 49.0Missense obs/exp: 246 / 475.8Syn Z: 1.04

Background carrier burden — how many people carry a rare variant somewhere in ATP6V0A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 69

778 rare PASS variants

Rare truncating (LoF)

1 in 2,100

99 rare PASS variants

Rare synonymous (reference)

1 in 110

396 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP6V0A1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 93	1 in 2,800
South Asian	~43k	1 in 70	1 in 860
Remaining (unassigned)	~30k	1 in 75	1 in 6,000
European (Finnish)	~27k	1 in 150	≈ 1 in 8,900
Admixed American	~22k	1 in 64	1 in 1,800
African / African American	~21k	1 in 85	1 in 2,200
East Asian	~20k	1 in 91	1 in 390
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 83	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 21 coding exons well covered in gnomAD exomes; exons 4, 9 marginal. Genomes: all 21.? see exons ↓