ATP2B2

Chr 3AD

ATPase plasma membrane Ca2+ transporting 2

Also known as: DFNA82, PMCA2, PMCA2a, PMCA2i

NCBI Gene: 491 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

The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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

55 unique Pathogenic / Likely Pathogenic· 288 VUS of 630 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.06 (0.03–0.15)

0≤0.351.4

Missense OE?0.54 (0.50–0.59)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

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

This gene — mechanism propensity

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 · 80% 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.1

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

References

1.PMID 17208398 ↗

ClinVar Variant Classifications

630 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic26

VUS288

Likely Benign171

Benign98

Conflicting8

Pathogenic

Likely Pathogenic

288

VUS

171

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	26	3	0	0	29
Likely Pathogenic	18	7	1	0	26
VUS	2	270	16	0	288
Likely Benign	1	13	39	118	171
Benign	0	2	68	28	98
Conflicting	—				8
Total	47	295	124	146	620

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap ATP2B2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →