ATP1A3

Chr 19AD

ATPase Na+/K+ transporting subunit alpha 3

NCBI Gene: 478ENSG00000105409UniProt: P13637

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Primary Disease Associations & Inheritance

Alternating hemiplegia of childhood 2MIM #614820
AD
CAPOS syndromeMIM #601338
AD
Developmental and epileptic encephalopathy 99MIM #619606
AD
Dystonia-12MIM #128235
AD
UniProtDystonia 12
UniProtCerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss
1387
ClinVar variants
41
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— ATP1A3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
41 Pathogenic / Likely Pathogenic· 227 VUS of 1387 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.06LOEUF
pLI 1.000
Z-score 6.40
OE 0.00 (0.00–0.06)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
6.33Z-score
OE missense 0.29 (0.26–0.33)
186 obs / 635.1 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.00 (0.00–0.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.29 (0.26–0.33)
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.1.10
0≤1.21.6
LoF obs/exp: 0 / 47.7Missense obs/exp: 186 / 635.1Syn Z: -1.32

ClinVar Variant Classifications

1387 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic28
VUS227
Likely Benign217
Conflicting12
13
Pathogenic
28
Likely Pathogenic
227
VUS
217
Likely Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
5
5
0
13
Likely Pathogenic
7
20
1
0
28
VUS
6
185
29
7
227
Likely Benign
1
3
80
133
217
Benign
0
0
0
0
0
Conflicting
—12
Total17213115140497

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

View in ClinVar →

Protein Context — Lollipop Plot

ATP1A3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ATP1A3-related alternating hemiplegia of childhood

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Alternating hemiplegia of childhood 2

MIM #614820

Molecular basis of disorder known

Autosomal dominant

CAPOS syndrome

MIM #601338

Molecular basis of disorder known

Autosomal dominant

Developmental and epileptic encephalopathy 99

MIM #619606

Molecular basis of disorder known

Autosomal dominant

Dystonia-12

MIM #128235

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Phenotypic Continuum of ATP1A3-Related Disorders.
Vezyroglou A et al.·Neurology
2022Review
ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.
Vetro A et al.·Brain
2021
The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.
Pérez-Dueñas B et al.·Mov Disord
2022
Clinical and genetic architecture of a large cohort with auditory neuropathy.
Wang H et al.·Hum Genet
2024Cohort
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Dystonia.
Morgante F et al.·Continuum (Minneap Minn)
2013Review
ATP1A3-related disorders: An update.
Carecchio M et al.·Eur J Paediatr Neurol
2018Review
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.
Sun M et al.·Genet Med
2019Cohort
ATP1A3-Associated Paroxysmal Dystonia.
Ledoux MS·Tremor Other Hyperkinet Mov (N Y)
2024Case report
Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain.
You Y et al.·J Extracell Vesicles
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
DystoniaParkinsonism

Studies of the Variable Phenotypic Presentations of Rapid-Onset Dystonia Parkinsonism and Other Movement Disorders

RECRUITING
NCT00682513State University of New York at BuffaloStarted 2008-04
DystoniaDystonia; IdiopathicDystonia, Primary

Dystonia Genotype-Phenotype Correlation

RECRUITING
NCT03428009University of Texas Southwestern Medical CenterStarted 2018-03-01
Magnetic Resonance Imaging
Alternating Hemiplegia of Childhood

Oxygen As an Acute Treatment in Alternating Hemiplegia of Childhood

RECRUITING
NCT06248645Phase PHASE2Assistance Publique - Hôpitaux de ParisStarted 2024-09-16
OxygenPlacebo

External Resources

Links to major genomics databases and tools