ATP6V1B2

Chr 8AD

ATPase H+ transporting V1 subunit B2

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

NCBI Gene: 526ENSG00000147416UniProt: P21281

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]

Primary Disease Associations & Inheritance

Deafness, congenital, with onychodystrophy, autosomal dominantMIM #124480
AD
Zimmermann-Laband syndrome 2MIM #616455
AD
265
ClinVar variants
98
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ATP6V1B2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
98 Pathogenic / Likely Pathogenic· 120 VUS of 265 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.06–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.52–0.67)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.13
0≤1.21.6
LoF obs/exp: 4 / 31.9Missense obs/exp: 172 / 291.4Syn Z: -1.05

ClinVar Variant Classifications

265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic85
Likely Pathogenic13
VUS120
Likely Benign21
Benign21
Conflicting5
85
Pathogenic
13
Likely Pathogenic
120
VUS
21
Likely Benign
21
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
80
0
85
Likely Pathogenic
0
8
5
0
13
VUS
3
98
19
0
120
Likely Benign
0
5
5
11
21
Benign
0
1
18
2
21
Conflicting
—5
Total311712713265

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

View in ClinVar →

Protein Context — Lollipop Plot

ATP6V1B2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATP6V1B2-related Zimmermann-Laband syndrome

strong
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, congenital, with onychodystrophy, autosomal dominant

MIM #124480

Molecular basis of disorder known

Autosomal dominant

Zimmermann-Laband syndrome 2

MIM #616455

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
Carpentieri G et al.·HGG Adv
2024Case report
ATP6V1B2-related epileptic encephalopathy.
Inuzuka LM et al.·Epileptic Disord
2020Case report
DOORS syndrome and a recurrent truncating ATP6V1B2 variant.
Beauregard-Lacroix E et al.·Genet Med
2021
A novel pathogenic ATP6V1B2 variant: Widening the genotypic spectrum of the epileptic neurodevelopmental phenotype.
Veltra D et al.·Am J Med Genet A
2022Case report
Single Administration of AAV-mAtp6v1b2 Gene Therapy Rescues Hearing and Vestibular Disorders Caused by Atp6v1b2-Induced Lysosomal Dysfunction in Hair Cells.
Wei G et al.·Adv Sci (Weinh)
2025
Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes.
Gao X et al.·Hum Genet
2022Review
ATP6V1B2-related disorders featuring Lennox-Gastaut-syndrome: A case-based overview.
Amore G et al.·Brain Dev
2023Case report
Epilepsy due to potential loss of ATP6V1B2 function with mechanistic insight by a Drosophila Vha55 model.
Sheng W et al.·Clin Genet
2024Functional
Clinical and genetic evaluations of Zimmermann-Laband syndrome with gingival fibromatosis: a rare case report.
Gu Y et al.·J Clin Pediatr Dent
2024Case report
A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.
Zhao W et al.·EBioMedicine
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools