ATP2C1

Chr 3AD

ATPase secretory pathway Ca2+ transporting 1

Also known as: ATP2C1A, BCPM, HHD, PMR1, SPCA1, hSPCA1

NCBI Gene: 27032 ENSG00000017260 UniProt: P98194 OMIM: 604384

The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium ions. Defects in this gene cause Hailey-Hailey disease, an autosomal dominant disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.181 OMIM phenotype

Clinical Summary— ATP2C1

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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

57 unique Pathogenic / Likely Pathogenic· 152 VUS of 355 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?

0.18LOEUF

pLI 1.000

Z-score 6.43

OE 0.09 (0.04–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.67Z-score

OE missense 0.54 (0.49–0.60)

280 obs / 514.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.18)

0≤0.351.4

Missense OE?0.54 (0.49–0.60)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 5 / 57.7Missense obs/exp: 280 / 514.5Syn Z: 0.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATP2C1-related Hailey-Hailey diseaseLOFAD

This gene — mechanism propensity

0.5575th %ile

GOF

0.6736th %ile

LOF

0.52top 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 · 81% of P/LP variants are LoF · LOEUF 0.18

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

LOFA high frequency of the last type of mutation supported a haploinsufficiency pathogenesis consistent with the complete deletion of the gene in 1 kindred and further suggested that calcium pumps of the PMR1 family function as monomers.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 10615129 ↗

ClinVar Variant Classifications

355 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic16

VUS152

Likely Benign24

Benign75

Conflicting4

Pathogenic

Likely Pathogenic

152

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	3	3	0	41
Likely Pathogenic	11	3	2	0	16
VUS	4	111	31	6	152
Likely Benign	1	4	8	11	24
Benign	0	5	65	5	75
Conflicting	—				4
Total	51	126	109	22	312

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap ATP2C1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →