ATP6V0C

Chr 16AD

ATPase H+ transporting V0 subunit c

Also known as: ATP6C, ATP6L, ATPL, EPEO3, VATL, VPPC, Vma3

NCBI Gene: 527 ENSG00000185883 UniProt: P27449 OMIM: 108745

The protein forms the proton-conducting pore of the V0 complex in vacuolar H+-ATPase, which acidifies intracellular compartments and maintains cellular pH homeostasis. Mutations cause autosomal dominant early-onset epilepsy with or without developmental delay, affecting the nervous system primarily in infancy or early childhood. The gene shows moderate constraint against loss-of-function variants (pLI 0.74, LOEUF 0.67), indicating that complete loss of function is somewhat selected against in the population.

GeneReviews 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. This gene encodes the V0 subunit c. Alternative splicing results in transcript variants. Pseudogenes have been identified on chromosomes 6 and 17. [provided by RefSeq, Nov 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.671 OMIM phenotype

Clinical Summary— ATP6V0C

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.74) — some intolerance to loss-of-function variants.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 30 VUS of 56 total submissions

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GeneReview available — ATP6V0C

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.67LOEUF

pLI 0.742

Z-score 1.96

OE 0.00 (0.00–0.67)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

2.99Z-score

OE missense 0.19 (0.14–0.28)

21 obs / 108.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.67)

0≤0.351.4

Missense OE?0.19 (0.14–0.28)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 0 / 4.5Missense obs/exp: 21 / 108.5Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP6V0C-related developmental disorderLOFAD

This gene — mechanism propensity

0.7325th %ile

GOF

0.6833th %ile

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

56 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic10

VUS30

Likely Benign2

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	6	0	0	10
Likely Pathogenic	3	7	0	0	10
VUS	4	24	2	0	30
Likely Benign	0	0	0	2	2
Benign	0	0	0	0	0
Conflicting	—				1
Total	11	37	2	2	53

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap ATP6V0C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →