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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

OMIM ResearchGenerating clinical summary…

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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Clinical Trials

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

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?

0.06LOEUF

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 OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.29 (0.26–0.33)

0≤0.61.4

Synonymous OE?1.10

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

This gene — mechanism propensity

0.4090th %ile

GOF

0.6639th %ile

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). 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 · 1 literature citation

LOFLOEUF 0.06

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 syndrome1

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

References