ATP1A2

Chr 1ADAR

ATPase Na+/K+ transporting subunit alpha 2

Also known as: DEE98, FARIMPD, FHM2, MHP2

NCBI Gene: 477 ENSG00000018625 UniProt: P50993

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]

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

596

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

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

⚡

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

50 Pathogenic / Likely Pathogenic· 287 VUS of 596 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.22–0.49)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.45 (0.41–0.50)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99

0≤1.21.6

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

ClinVar Variant Classifications

596 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic31

VUS287

Likely Benign180

Benign56

Conflicting23

Pathogenic

Likely Pathogenic

287

VUS

180

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	5	5	0	19
Likely Pathogenic	10	20	1	0	31
VUS	4	224	53	6	287
Likely Benign	0	4	75	101	180
Benign	0	0	56	0	56
Conflicting	—				23
Total	23	253	190	107	596

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

View in ClinVar →

Protein Context — Lollipop Plot

ATP1A2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ATP1A2-related epileptic encephalopathy

moderate

ADGain Of FunctionAltered Gene Product Structure

Dev. Disorders

G2P ↗

splice region variantmissense variant

ATP1A2-related neuronal migration disorder with epilepsy

strong

ARUndeterminedAbsent Gene Product

Dev. Disorders

G2P ↗

stop gained NMD triggeringframeshift variant NMD triggering

ATP1A2-related migraine, familial hemiplegic

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2

MIM #182340 · *

Alternating hemiplegia of childhood 1

MIM #104290