ATP6V0B

Chr 1

ATPase H+ transporting V0 subunit b

Also known as: ATP6F, HATPL, VMA16

NCBI Gene: 533 ENSG00000117410 UniProt: Q99437 OMIM: 603717

This gene encodes a proton-conducting pore subunit of the vacuolar ATPase (V-ATPase) complex that acidifies intracellular organelles and maintains cellular pH homeostasis, functioning in essential processes including protein sorting, endocytosis, and synaptic vesicle acidification. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities (DEE112), typically presenting in early infancy with severe seizures, developmental delays, and progressive neurodegeneration. The gene is highly constrained against loss-of-function variants, reflecting its critical role in cellular function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a portion of the V0 domain of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Activity of this enzyme is necessary for such varied processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.28

Clinical Summary— ATP6V0B

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

14 VUS of 46 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.969

Z-score 3.04

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint?

1.81Z-score

OE missense 0.53 (0.43–0.66)

63 obs / 118.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.53 (0.43–0.66)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 0 / 10.8Missense obs/exp: 63 / 118.6Syn Z: 0.28

This gene — mechanism propensity

0.6937th %ile

GOF

0.6540th %ile

LOF

0.4233th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.28

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

46 submitted variants in ClinVar

ClinVar

Classification Summary

VUS14

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	14	0	14
Likely Benign	0	1	1
Benign	0	0	0
Total	14	1	15

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap ATP6V0B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →