ATP11A

Chr 13

ATPase phospholipid transporting 11A

Also known as: ATPIH, ATPIS, AUNA2, DFNA84, HLD24

NCBI Gene: 23250 ENSG00000068650 UniProt: P98196

This protein is a P4-ATPase flippase that transports phospholipids from the outer to inner leaflet of cell membranes and contributes to muscle cell development. Autosomal dominant mutations cause hearing loss (deafness or auditory neuropathy) and possibly hypomyelinating leukodystrophy. The gene is highly constrained against loss-of-function variants (LOEUF 0.467), suggesting intolerance to protein disruption.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is an integral membrane ATPase. The encoded protein is probably phosphorylated in its intermediate state and likely drives the transport of ions such as calcium across membranes. [provided by RefSeq, Apr 2022]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— ATP11A

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 205 VUS of 308 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.000

Z-score 5.19

OE 0.33 (0.24–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.37Z-score

OE missense 0.85 (0.80–0.91)

592 obs / 693.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.24–0.47)

0≤0.351.4

Missense OE?0.85 (0.80–0.91)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 23 / 69.8Missense obs/exp: 592 / 693.3Syn Z: -1.13

This gene — mechanism propensity

0.74top 25%

GOF

0.78top 25%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). 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 · 33% of P/LP variants are LoF · LOEUF 0.47

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.

Literature Evidence

LOFHaploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation.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 35278131 ↗

ClinVar Variant Classifications

308 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS205

Likely Benign47

Benign16

Conflicting7

Pathogenic

Likely Pathogenic

205

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	1	0	4
Likely Pathogenic	1	1	0	0	2
VUS	3	200	2	0	205
Likely Benign	1	17	6	23	47
Benign	0	3	2	11	16
Conflicting	—				7
Total	6	223	11	34	281

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

View in ClinVar →

120 pathogenic / likely-pathogenic (of 136) ClinVar copy-number / structural variants overlap ATP11A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →