ATP6V1B2

Chr 8AD

ATPase H+ transporting V1 subunit B2

Also known as: ATP6B1B2, ATP6B2, DOOD, HO57, VATB, VPP3, Vma2, ZLS2

NCBI Gene: 526 ENSG00000147416 UniProt: P21281 OMIM: 606939

ATP6V1B2 encodes a non-catalytic subunit of the V1 complex of vacuolar H+-ATPase, which acidifies intracellular compartments and, in some cells, the extracellular environment. Autosomal dominant mutations cause congenital deafness with onychodystrophy and Zimmermann-Laband syndrome 2. The gene is highly constrained against loss-of-function variants (pLI = 0.99), indicating that such variants are likely pathogenic.

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, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, congenital, with onychodystrophy, autosomal dominantMIM #124480

Zimmermann-Laband syndrome 2MIM #616455

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Deafness, congenital, with onychodystrophy, autosomal dominant; Zimmermann-Laband syndrome 2; no ClinGen or GenCC tier

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.29

LOEUF· LoF intol.

DN*

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.992

Z-score 4.58

OE 0.13 (0.06–0.29)

Highly constrained

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

Missense Constraint?

2.49Z-score

OE missense 0.59 (0.52–0.67)

172 obs / 291.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.29)

0≤0.351.4

Missense OE?0.59 (0.52–0.67)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 4 / 31.9Missense obs/exp: 172 / 291.4Syn Z: -1.05

Background carrier burden — how many people carry a rare variant somewhere in ATP6V1B2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

528 rare PASS variants

Rare truncating (LoF)

1 in 5,100

56 rare PASS variants

Rare synonymous (reference)

1 in 220

309 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP6V1B2. 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 180	1 in 5,500
South Asian	~43k	1 in 110	≈ 1 in 9,900
Remaining (unassigned)	~30k	1 in 160	≈ 1 in 10,000
European (Finnish)	~27k	1 in 290	≈ 1 in 8,900
Admixed American	~22k	1 in 130	1 in 2,400
African / African American	~21k	1 in 170	≈ 1 in 9,300
East Asian	~20k	1 in 160	≈ 1 in 4,200
Ashkenazi Jewish	~13k	1 in 560	none seen
Middle Eastern	~2,884	1 in 180	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): 13 of 14 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 14.? see exons ↓