ATP1A3

Chr 19AD

ATPase Na+/K+ transporting subunit alpha 3

Also known as: AHC2, CAPOS, DEE99, DYT12, RDP

NCBI Gene: 478 ENSG00000105409 UniProt: P13637 OMIM: 182350

The ATP1A3 gene encodes the alpha-3 subunit of the sodium-potassium ATPase pump, which establishes and maintains electrochemical gradients of sodium and potassium ions across the plasma membrane that are essential for neuronal excitability. Autosomal dominant mutations cause alternating hemiplegia of childhood, CAPOS syndrome, developmental and epileptic encephalopathy, and dystonia through loss of function mechanisms. The gene is extremely intolerant to loss-of-function variants, indicating that haploinsufficiency is the primary pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.064 OMIM phenotypes

Clinical Summary— ATP1A3

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Gene-Disease Validity (ClinGen)

ATP1A3-associated neurological disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

42 unique Pathogenic / Likely Pathogenic· 227 VUS of 500 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATP1A3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.06LOEUF

pLI 1.000

Z-score 6.40

OE 0.00 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

6.33Z-score

OE missense 0.29 (0.26–0.33)

186 obs / 635.1 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.06)

0≤0.351.4

Missense OE0.29 (0.26–0.33)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 0 / 47.7Missense obs/exp: 186 / 635.1Syn Z: -1.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP1A3-related alternating hemiplegia of childhoodOTHERAD

0.4090th %ile

GOF

0.6639th %ile

LOF

0.61top 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.

LOF31% of P/LP variants are LoF · LOEUF 0.06

GOFprediction above median · 1 literature citation

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

GOFA novel recurrent mutation in ATP1A3 causes CAPOS syndromePMID:24468074

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.