ATP2A1

Chr 16AR

ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1

Also known as: ATP2A, SERCA1

NCBI Gene: 487 ENSG00000196296 UniProt: O14983 OMIM: 108730

This gene encodes SERCA1, a calcium ATPase pump that translocates calcium from the cytosol into the sarcoplasmic reticulum lumen in muscle cells, which is essential for muscle relaxation after contraction. Biallelic mutations cause Brody myopathy, an autosomal recessive disorder characterized by progressive impairment of muscle relaxation during exercise. The gene shows relatively low constraint to loss-of-function variation (LOEUF 0.833), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, 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 muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.831 OMIM phenotype

Clinical Summary— ATP2A1

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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

74 unique Pathogenic / Likely Pathogenic· 428 VUS of 949 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.50

OE 0.61 (0.46–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.54Z-score

OE missense 0.82 (0.76–0.89)

496 obs / 602.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.46–0.83)

0≤0.351.4

Missense OE?0.82 (0.76–0.89)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 30 / 48.8Missense obs/exp: 496 / 602.3Syn Z: 0.04

This gene — mechanism propensity

0.78top 25%

GOF

0.84top 5%

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

949 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44

Likely Pathogenic30

VUS428

Likely Benign362

Benign44

Conflicting29

Pathogenic

Likely Pathogenic

428

VUS

362

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	2	7	0	44
Likely Pathogenic	29	1	0	0	30
VUS	4	396	20	8	428
Likely Benign	0	2	162	198	362
Benign	0	2	38	4	44
Conflicting	—				29
Total	68	403	227	210	937

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

View in ClinVar →

118 pathogenic / likely-pathogenic (of 162) ClinVar copy-number / structural variants overlap ATP2A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →