ATP2B2

Chr 3AD

ATPase plasma membrane Ca2+ transporting 2

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.151 OMIM phenotype
Clinical SummaryATP2B2
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Gene-Disease Validity (ClinGen)
autosomal dominant nonsyndromic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.15LOEUF
pLI 1.000
Z-score 6.33
OE 0.06 (0.030.15)
Highly constrained

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

Missense Constraint
4.55Z-score
OE missense 0.54 (0.500.59)
431 obs / 791.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.06 (0.030.15)
00.351.4
Missense OE0.54 (0.500.59)
00.61.4
Synonymous OE1.05
01.21.6
LoF obs/exp: 3 / 52.5Missense obs/exp: 431 / 791.0Syn Z: -0.80
DN
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.

ClinVar Variant Classifications

400 submitted variants in ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic10
VUS220
Likely Benign115
Benign23
Conflicting5
26
Pathogenic
10
Likely Pathogenic
220
VUS
115
Likely Benign
23
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
2
11
0
26
Likely Pathogenic
5
3
2
0
10
VUS
2
205
13
0
220
Likely Benign
1
8
28
78
115
Benign
0
1
7
15
23
Conflicting
5
Total212196193399

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

View in ClinVar →

Protein Context — Lollipop Plot

ATP2B2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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