ATP1A3

Chr 19AD

ATPase Na+/K+ transporting subunit alpha 3

Also known as: AHC2, CAPOS, DEE99, DYT12, RDP

NCBI Gene: 478 ENSG00000105409 UniProt: P13637 OMIM: 182350

The ATP1A3 gene encodes the alpha-3 subunit of the sodium-potassium ATPase pump, which establishes and maintains electrochemical gradients of sodium and potassium ions across the plasma membrane that are essential for neuronal excitability. Autosomal dominant mutations cause alternating hemiplegia of childhood, CAPOS syndrome, developmental and epileptic encephalopathy, and dystonia through loss of function mechanisms. The gene is extremely intolerant to loss-of-function variants, indicating that haploinsufficiency is the primary pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Alternating hemiplegia of childhood 2MIM #614820

CAPOS syndromeMIM #601338

Developmental and epileptic encephalopathy 99MIM #619606

Dystonia-12MIM #128235

UniProtDystonia 12

UniProtCerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · ATP1A3-associated neurological disorder · AD · ClinGen 2022
Definitive · alternating hemiplegia of childhood 2 · AD · Ambry Genetics
Definitive · cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome · AD · Ambry Genetics
Strong · developmental and epileptic encephalopathy 99 · AD · Ambry Genetics
Limited · complex neurodevelopmental disorder · AR · Ambry Genetics — not for standalone diagnostic reporting

+3 more curated pairs

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.06

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — ATP1A3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.29 (0.26–0.33)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 0 / 47.7Missense obs/exp: 186 / 635.1Syn Z: -1.32

Background carrier burden — how many people carry a rare variant somewhere in ATP1A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

563 rare PASS variants

Rare truncating (LoF)

1 in 9,000

37 rare PASS variants

Rare synonymous (reference)

1 in 71

574 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP1A3. 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 150	1 in 11,000
South Asian	~43k	1 in 190	≈ 1 in 42,000
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 30,000
European (Finnish)	~27k	1 in 290	1 in 5,300
Admixed American	~22k	1 in 190	≈ 1 in 18,000
African / African American	~21k	1 in 180	≈ 1 in 10,000
East Asian	~20k	1 in 320	none seen
Ashkenazi Jewish	~13k	1 in 380	none seen
Middle Eastern	~2,884	1 in 220	none seen

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 ↓