ATP1A2

Chr 1ADAR

ATPase Na+/K+ transporting subunit alpha 2

Also known as: DEE98, FARIMPD, FHM2, MHP2

NCBI Gene: 477 ENSG00000018625 UniProt: P50993 OMIM: 182340

The ATP1A2 gene encodes the alpha-2 subunit of Na+/K+-ATPase, which establishes and maintains electrochemical gradients of sodium and potassium ions across plasma membranes that are essential for neuronal excitability. Heterozygous mutations cause autosomal dominant familial hemiplegic migraine type 2 and alternating hemiplegia of childhood through a gain-of-function mechanism, while biallelic mutations result in autosomal recessive developmental and epileptic encephalopathy and severe fetal akinesia syndromes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Alternating hemiplegia of childhood 1MIM #104290

Developmental and epileptic encephalopathy 98MIM #619605

Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic faciesMIM #619602

Migraine, familial basilarMIM #602481

Migraine, familial hemiplegic, 2MIM #602481

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies · AR · ClinGen 2025
Definitive · hemiplegic migraine-developmental and epileptic encephalopathy spectrum · AD · ClinGen 2024
Definitive · migraine, familial hemiplegic, 2 · AD · Ambry Genetics
Strong · developmental and epileptic encephalopathy 98 · AD · Ambry Genetics

+3 more curated pairs

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

Multiple*

Mechanism· G2P

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GeneReview available — ATP1A2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.49LOEUF

pLI 0.000

Z-score 4.37

OE 0.33 (0.22–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.77Z-score

OE missense 0.45 (0.41–0.50)

274 obs / 604.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.33 (0.22–0.49)

0≤0.351.4

Missense OE?0.45 (0.41–0.50)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 16 / 49.1Missense obs/exp: 274 / 604.0Syn Z: 0.07

Background carrier burden — how many people carry a rare variant somewhere in ATP1A2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

759 rare PASS variants

Rare truncating (LoF)

1 in 2,500

113 rare PASS variants

Rare synonymous (reference)

1 in 68

528 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP1A2. 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 92	1 in 2,300
South Asian	~43k	1 in 95	1 in 1,600
Remaining (unassigned)	~30k	1 in 110	1 in 820
European (Finnish)	~27k	1 in 290	1 in 2,900
Admixed American	~22k	1 in 93	≈ 1 in 11,000
African / African American	~21k	1 in 120	1 in 2,200
East Asian	~20k	1 in 83	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 360	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 93	≈ 1 in 2,900

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): All 23 coding exons well covered in gnomAD exomes and genomes.? see exons ↓