ATP1A2

Chr 1ADAR

ATPase Na+/K+ transporting subunit alpha 2

Also known as: DEE98, FARIMPD, FHM2, MHP2

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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismAD/ARLOEUF 0.495 OMIM phenotypes
Clinical SummaryATP1A2
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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

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
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ClinVar Variants
136 unique Pathogenic / Likely Pathogenic· 674 VUS of 1562 total submissions
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GeneReview available — ATP1A2
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Missense constrained — critical functional residues
LoF Constraint?
0.49LOEUF
pLI 0.000
Z-score 4.37
OE 0.33 (0.220.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
4.77Z-score
OE missense 0.45 (0.410.50)
274 obs / 604.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.33 (0.220.49)
00.351.4
Missense OE?0.45 (0.410.50)
00.61.4
Synonymous OE?0.99
01.21.6
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

DN
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 · 46% of P/LP variants are LoF · 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.

ClinVar Variant Classifications

1562 submitted variants in ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic79
VUS674
Likely Benign562
Benign101
Conflicting85
57
Pathogenic
79
Likely Pathogenic
674
VUS
562
Likely Benign
101
Benign
85
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
29
28
0
0
57
Likely Pathogenic
34
44
1
0
79
VUS
8
558
94
14
674
Likely Benign
0
8
260
294
562
Benign
0
0
95
6
101
Conflicting
85
Total716384503141,558

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap ATP1A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ATP1A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →