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

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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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 OE0.00 (0.00–0.28)

0≤0.351.4

Missense OE0.53 (0.43–0.66)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

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

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.