ATP2A3

Chr 17

ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3

Also known as: SERCA3

NCBI Gene: 489 ENSG00000074370 UniProt: Q93084 OMIM: 601929

This gene encodes a SERCA calcium-ATPase that transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum lumen, contributing to calcium sequestration during muscular excitation and contraction. Mutations cause cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome) and X-linked dystonia-parkinsonism, both following X-linked inheritance patterns. The gene is highly intolerant to loss-of-function mutations, and the associated disorders primarily affect the nervous system with movement abnormalities and sensory deficits.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.66

Clinical Summary— ATP2A3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

132 VUS of 206 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.51

OE 0.46 (0.33–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.83Z-score

OE missense 0.80 (0.74–0.86)

537 obs / 670.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.33–0.66)

0≤0.351.4

Missense OE?0.80 (0.74–0.86)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 23 / 49.7Missense obs/exp: 537 / 670.5Syn Z: -2.53

This gene — mechanism propensity

0.78top 25%

GOF

0.82top 10%

LOF

0.2092th %ile

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

GOFprediction above median

DNprediction 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.

ClinVar Variant Classifications

206 submitted variants in ClinVar

ClinVar

Classification Summary

VUS132

Likely Benign34

Benign25

Conflicting2

132

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	132	0	0	132
Likely Benign	0	7	4	23	34
Benign	0	4	3	18	25
Conflicting	—				2
Total	0	143	7	41	193

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap ATP2A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →