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.

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2DDMIM #618036

Hypomagnesemia, seizures, and impaired intellectual development 2MIM #618314

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Charcot-Marie-tooth disease, axonal, type 2DD · AD · ClinGen 2026

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in ATP1A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

571 rare PASS variants

Rare truncating (LoF)

1 in 6,100

54 rare PASS variants

Rare synonymous (reference)

1 in 60

512 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP1A1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 330	1 in 6,200
South Asian	~43k	1 in 210	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 390	none seen
European (Finnish)	~27k	1 in 380	1 in 1,700
Admixed American	~22k	1 in 150	≈ 1 in 22,000
African / African American	~21k	1 in 250	≈ 1 in 9,300
East Asian	~20k	1 in 250	1 in 1,900
Ashkenazi Jewish	~13k	1 in 400	none seen
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 23 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 23.? see exons ↓