ATP2B3

Chr X

ATPase plasma membrane Ca2+ transporting 3

Also known as: CFAP39, CLA2, OPCA, PMCA3, PMCA3a, SCAX1

NCBI Gene: 492 ENSG00000067842 UniProt: Q16720

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

Primary Disease Associations & Inheritance

UniProtSpinocerebellar ataxia, X-linked 1

183

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— ATP2B3

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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

32 Pathogenic / Likely Pathogenic· 102 VUS of 183 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Some data sources returned errors (2)

omim: Error: OMIM fetch failed: 429

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.

0.22LOEUF

pLI 0.999

Z-score 5.00

OE 0.09 (0.04–0.22)

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.

2.75Z-score

OE missense 0.68 (0.63–0.74)

405 obs / 593.2 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.0.09 (0.04–0.22)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.63–0.74)

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.1.01

0≤1.21.6

LoF obs/exp: 3 / 34.9Missense obs/exp: 405 / 593.2Syn Z: -0.14