ATP1A1

Chr 1AD

ATPase Na+/K+ transporting subunit alpha 1

Also known as: CMT2DD, HOMGSMR2

NCBI Gene: 476 ENSG00000163399 UniProt: P05023 OMIM: 182310

The alpha 1 subunit of Na+/K+-ATPase is the catalytic component that hydrolyzes ATP to exchange sodium and potassium ions across the plasma membrane, creating electrochemical gradients essential for neuronal excitability and cellular transport. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2DD and hypomagnesemia with seizures and intellectual disability. This gene is highly constrained against loss-of-function variants (pLI ~1.0), reflecting its critical role in cellular physiology.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.122 OMIM phenotypes

Clinical Summary— ATP1A1

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Gene-Disease Validity (ClinGen)

charcot-marie-tooth disease, axonal, type 2DD · ADModerate

Moderate evidence — consider for supplementary testing

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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

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATP1A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.12LOEUF

pLI 1.000

Z-score 6.43

OE 0.04 (0.01–0.12)

Highly constrained

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

Missense Constraint

6.22Z-score

OE missense 0.29 (0.25–0.32)

171 obs / 599.1 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.12)

0≤0.351.4

Missense OE0.29 (0.25–0.32)

0≤0.61.4

Synonymous OE1.12

0≤1.21.6

LoF obs/exp: 2 / 52.0Missense obs/exp: 171 / 599.1Syn Z: -1.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongATP1A1-related renal hypomagnesemia refractory seizures and intellectual disabilityOTHERAD

0.4487th %ile

GOF

0.5954th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.12

GOF1 literature citation

Literature Evidence

GOFMutations in the Na(+)/K(+)-ATPase subunit ATP1A1 and the plasma membrane Ca(2+)-ATPase ATP2B3 similarly cause Na(+) or H(+) permeability and depolarization, whereas mutations in the Ca(2+) channel CACNA1D directly lead to increased calcium influx.PMID:27445978

LOFLassuthova et al. (2018) suggested that ATP1A1 mutations cause a reduction in Na+/K(+)-ATPase activity, thus reducing the Na+ gradient across the axonal membrane and potentially causing increased intracellular axonal Ca(2+) levels, which would be toxic to the cell and cause axonal degeneration. The PMID:29499166

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