ATP2B1

Chr 12AD

ATPase plasma membrane Ca2+ transporting 1

Also known as: MRD66, PMCA1, PMCA1kb

NCBI Gene: 490 ENSG00000070961 UniProt: P20020

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 1. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 66MIM #619910

Active trials

Pathogenic / LP

255

ClinVar variants

Pubs (1 yr)

5.3

Missense Z· constrained

0.08

LOEUF· LoF intolerant

Clinical Summary— ATP2B1

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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

50 Pathogenic / Likely Pathogenic· 187 VUS of 255 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.08LOEUF

pLI 1.000

Z-score 6.83

OE 0.02 (0.01–0.08)

Highly constrained

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

Missense Constraint

5.29Z-score

OE missense 0.42 (0.38–0.46)

271 obs / 650.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.02 (0.01–0.08)

0≤0.351.4

Missense OE0.42 (0.38–0.46)

0≤0.61.4

Synonymous OE0.91

0≤1.21.6

LoF obs/exp: 1 / 56.3Missense obs/exp: 271 / 650.9Syn Z: 1.05

LOFGOF

Badonyi & Marsh 2024 ↗

0.3693th %ile

GOF

0.6638th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 38% of P/LP variants are LoF · LOEUF 0.08

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.

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