ATP13A5

Chr 3

ATPase 13A5

NCBI Gene: 344905 ENSG00000187527 OMIM: 619119

This gene encodes a member of the P5 subfamily of P-type transport ATPases. P-type ATPases form a large superfamily of cation and lipid pumps that transport inorganic cations and other substrates across cell membranes. P5 ATPases are localized to membranes of the endoplasmic reticulum (ER) and serve many important functions including transport of cargo proteins to the Golgi, glycosylation and cell wall biosynthesis, control of protein insertion orientation, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) degradation, and sensitivity to unfolded protein response (UPR) activators. The encoded protein is organized into three cytoplasmic domains (A, P, and N) and two membrane-embedded domains (T and S). The N-domain binds ATP and serves as a built-in protein kinase, which phosphorylates the P-domain. The A-domain is an intrinsic protein phosphatase, which dephosphorylates the P-domain once during each catalytic cycle. [provided by RefSeq, Jul 2017]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.29

Clinical Summary— ATP13A5

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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

155 VUS of 176 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?

1.29LOEUF

pLI 0.000

Z-score -0.44

OE 1.06 (0.87–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.61Z-score

OE missense 0.93 (0.87–1.00)

601 obs / 644.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.06 (0.87–1.29)

0≤0.351.4

Missense OE?0.93 (0.87–1.00)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 72 / 68.0Missense obs/exp: 601 / 644.3Syn Z: 0.66

This gene — mechanism propensity

0.7327th %ile

GOF

0.73top 25%

LOF

0.2969th %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

176 submitted variants in ClinVar

ClinVar

Classification Summary

VUS155

Likely Benign9

Benign2

155

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	0	155	0	155
Likely Benign	1	6	2	9
Benign	1	0	1	2
Total	2	161	3	166

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ATP13A5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →