ATP2B2

Chr 3AD

ATPase plasma membrane Ca2+ transporting 2

ENSG00000157087 UniProt: Q01814 OMIM: 108733

ATP2B2 encodes plasma membrane calcium ATPase isoform 2, which uses ATP to pump calcium ions out of cells and is critical for maintaining calcium homeostasis in the cerebellar circuit, vestibular system, and cochlear hair cells. Mutations cause autosomal dominant deafness (DFNA82), reflecting the protein's essential role in auditory and vestibular function. The gene is extremely intolerant to loss-of-function variants (pLI >0.99), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— ATP2B2

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 220 VUS of 400 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.15LOEUF

pLI 1.000

Z-score 6.33

OE 0.06 (0.03–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

4.55Z-score

OE missense 0.54 (0.50–0.59)

431 obs / 791.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.06 (0.03–0.15)

0≤0.351.4

Missense OE0.54 (0.50–0.59)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 3 / 52.5Missense obs/exp: 431 / 791.0Syn Z: -0.80

0.5279th %ile

GOF

0.72top 25%

LOF

0.57top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function 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.

LOF1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.15

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.

Literature Evidence

LOFAlthough other genes in this region remain candidates, we conclude that haploinsufficiency of ATP2B2 is the most likely cause of SNHL in 3p-syndrome.PMID:17208398

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.