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

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 1 subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 364 VUS of 962 total submissions

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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 OE?0.04 (0.01–0.12)

0≤0.351.4

Missense OE?0.29 (0.25–0.32)

0≤0.61.4

Synonymous OE?1.12

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

This gene — mechanism propensity

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 · 96% of P/LP are missense

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.1

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 2

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

References

ClinVar Variant Classifications

962 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic17

VUS364

Likely Benign488

Benign47

Conflicting11

Pathogenic

Likely Pathogenic

364

VUS

488

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	10	0	0	10
Likely Pathogenic	1	16	0	0	17
VUS	22	302	35	5	364
Likely Benign	1	11	198	278	488
Benign	0	1	40	6	47
Conflicting	—				11
Total	24	340	273	289	937

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap ATP1A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →