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.

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.495 OMIM phenotypes

Clinical Summary— ATP1A2

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Gene-Disease Validity (ClinGen)

hemiplegic migraine-developmental and epileptic encephalopathy spectrum · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateATP1A2-related epileptic encephalopathyGOFAD

strongATP1A2-related neuronal migration disorder with epilepsyOTHERAR

definitiveATP1A2-related migraine, familial hemiplegicLOFAD

This gene — mechanism propensity

0.80top 10%

GOF

0.82top 10%

LOF

0.2091th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative 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

DNprediction above median

LOF1 literature citation · LOEUF 0.49

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

GOFIonic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases1

LOFHaploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.2

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

References