ATP8A2

Chr 13AR

ATPase phospholipid transporting 8A2

Also known as: ATP, ATPIB, CAMRQ4, IB, ML-1

NCBI Gene: 51761 ENSG00000132932 UniProt: Q9NTI2 OMIM: 605870

ATP8A2 encodes a P4-ATPase flippase that translocates phospholipids (particularly phosphatidylserine) from the outer to inner membrane leaflet to maintain membrane asymmetry and support vesicle trafficking in neuronal cells. Mutations cause cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4 with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants and the protein is required for normal visual and auditory function as well as photoreceptor and inner ear spiral ganglion cell survival.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.601 OMIM phenotype

Clinical Summary— ATP8A2

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Gene-Disease Validity (ClinGen)

cerebellar ataxia, intellectual disability, and dysequilibrium · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 4.39

OE 0.45 (0.34–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.30Z-score

OE missense 0.75 (0.69–0.81)

490 obs / 655.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.45 (0.34–0.60)

0≤0.351.4

Missense OE?0.75 (0.69–0.81)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 33 / 73.7Missense obs/exp: 490 / 655.4Syn Z: 0.61

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP8A2-related cerebellar ataxia, intellectual developmental disorder, and dysequilibrium syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.78top 25%

LOF

0.2386th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.