ATP1A2
protein-codingATPase Na+/K+ transporting subunit alpha 2, the group of ATPase Na+/K+ transporting subunits
Gene summary
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]
- MHP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030472
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007087
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007087
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011232
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030472
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0859204
Submitter: ClinGen
ATPase, Na+/K+ Transporting, Alpha-2 Polypeptide (ATP1A2; MIM#182340) is a subunit of a P-type cation transport ATPase integral for establishing and maintaining electrochemical gradients of Na and K across the plasma membrane. Single heterozygous pathogenic variants in ATP1A2 are definitively associated with “hemiplegic migraine-developmental and epileptic encephalopathy spectrum” (MONDO:0100539) as curated by the Epilepsy GCEP of ClinGen. Biallelic variants in ATP1A2 were first reported by Chatron, et.al., in 2019 in four neonates from two independent families with shared phenotypes of congenital microcephaly, CNS anomalies, and fetal akinesia sequence [PMID:31608932]. Since its initial report, biallelic ATP1A2 variants have been reported in 7 additional probands from 5 independent families with prenatal phenotypes including elevated nuchal translucency or nuchal thickening, microcephaly, polyhydramnios, hydrops, fetal growth restriction, fetal akinesia, dysmorphic features including hypertelorism and micrognathia, and CNS anomalies including polymicrogyria or other abnormalities of gyration, calcifications, and ventriculomegaly [PMID:31608932, 30690204, 37870493, 39046620, 38549198]. Neonatal seizures and neonatal demise due to respiratory insufficiency is also often observed in neonates with biallelic ATP1A2 variants. The presumed mechanism of disease is loss of function with affected probands harboring biallelic nonsense, frameshift, or canonical splice variants with only a single missense variant reported at the time of curation. Maximum genetic evidence of 12.0 points was reached based on literature evidence. Of note, several parents of probands with bialleic ATP1A2 variants reported history of migraines [PMID:31608932, 30690204, 37870493]. Functional evidence including biochemical function [PMID:12763872] and mouse models recapitulating the observed human phenotype [PMID:12805306, 15564586] were scored for an additional 2.5 points. Given this and its replication in the literature over time, ATP1A2 has been curated as Definitive for fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (MONDO:0859204) by the Prenatal Gene Curation Expert Panel (Gene-Disease Validity Standard Operating Procedures, Version 11) on 6/17/2025.
Inheritance Pattern: AD
Disease ID:MONDO:0011232
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859204
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011232
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0859204
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016241
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018925
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011232
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011232
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0030472
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0859204
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859204
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007087
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0100539
Submitter: ClinGen
*ATP1A2* was first reported in relation to autosomal dominant familial hemiplegic migraine in 2003 (De Fusco et al., PMID:12539047). Patients with hemiplegic migraines experience migraine headaches that are accompanied by temporary motor weakness. Since 2003, patients with variants in *ATP1A2* have also been reported with autosomal dominant alternating hemiplegia of childhood and autosomal dominant developmental and epileptic encephalopathy (PMIDs: 15174025, 33880529). Individuals with developmental and epileptic encephalopathy often experience seizures that onset in infancy and developmental delays. Alternating hemiplegia of childhood is characterized by episodes of paralysis that typically affect one side of the body, and commonly onsets in infancy or early childhood. There have been several reports of individuals with the same variant in *ATP1A2* and different phenotypes. For example, in one family, a father with an *ATP1A2* variant was reported to experience hemiplegic migraines and was noted to have typical cognition. His son with the same variant presented with developmental and epileptic encephalopathy, including seizure onset at six days of life and global developmental delays (PMID: 33493807). Currently, because a patient’s phenotype cannot easily be predicted based on their variant, we have curated cases of “familial hemiplegic migraine” (OMIM:602481), “alternating hemiplegia of childhood” (OMIM:104290), and “developmental and epileptic encephalopathy” (OMIM:619605) under the disease term “hemiplegic migraine-developmental and epileptic encephalopathy spectrum” (MONDO:0100539). Of note, there have also been reports of a relationship between biallelic variants in *ATP1A2* and autosomal recessive “fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies.” Due to differences in inheritance pattern and phenotypic variability, these cases have not been included in this curation. Variants in *ATP1A2* (missense, frameshift, nonsense, intronic) have been reported in at least 17 probands in 11 publications (12539047, 15843000, 16088919, 18056581, 21731499, 2313342, 24096472, 24498617, 33880529, 33493807, 33578253). Variants in this gene segregated with disease in at least 20 additional family members. Penetrance has been estimated at 81% for this condition (PMID: 16088919). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. While the disease mechanism is still unclear, Friedrich et al. (2016) state that some variants are “characterized by subtle changes in voltage dependence…In these cases, a shift of the pump current's I-V curve may entail loss-of-function in a particular voltage range, but gain-of-function in another” (PMID: 27445835). This gene-disease relationship is also supported by an animal model and in vitro functional assays. In summary, there is definitive evidence supporting the relationship between *ATP1A2* and autosomal dominant hemiplegic migraine-developmental and epileptic encephalopathy spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Epilepsy GCEP on January 19, 2021 (SOP Version 8). It was reevaluated and approved on January 16, 2024 (SOP Version 10) to include new case-level data to best capture the spectrum of disease, and to update the disease term from “familial hemiplegic migraine” to “hemiplegic migraine-developmental and epileptic encephalopathy spectrum.” The final classification of definitive did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0030472
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007087
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: Neurologic; Pharmacogenomic
Rationale: In Alternating hemiplegia of childhood, medical treatment (with calcium channel blockers) has been described as at least partially effective; Vasoconstricting agents (due to risk of stroke) and cerebral angiograophy (due to risk of precipitation of attack) should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP1A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000702.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 16 | 322 | 4 | 342 | ||
| missense | 26 | 75 | 583 | 28 | 1 | 713 |
| nonsense | 10 | 8 | 2 | 20 | ||
| start loss | 2 | 2 | ||||
| frameshift | 16 | 13 | 2 | 31 | ||
| splice donor/acceptor (+/-2bp) | 2 | 18 | 4 | 24 | ||
| Total | 54 | 114 | 609 | 350 | 5 | 1132 |
Highest pathogenic variant AF is 0.0000075244957
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000693.1 | 23 | MANE Select | |
| Ensembl | ENSP00000354490.3 | 23 | MANE Select | |
| Ensembl | ENSP00000376066.3 | 23 | Standard | |
| Ensembl | ENSP00000376066.3 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atp1a2a | Danio rerio | Structure: post-vent region Quality: curved dorsal abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Cardiac muscle contraction - Homo sapiens (human)
- Thyroid hormone synthesis - Homo sapiens (human)
- Protein digestion and absorption - Homo sapiens (human)
- Bile secretion - Homo sapiens (human)
Biological Process
- neurotransmitter uptake
- regulation of the force of heart contraction
- regulation of respiratory gaseous exchange by neurological system process
- potassium ion transport
- sodium ion transport
Molecular Function
- sodium:potassium-exchanging ATPase activity
- protein binding
- ATP binding
- drug binding
- ATPase activity
Cellular Component
- cytoplasm
- endosome
- plasma membrane
- sodium:potassium-exchanging ATPase complex
- caveola
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361216
- Coding exons
- 23
- Length
- 27833
- Individuals with no LoFs
- 125720
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 125748
- p
- 0.000111
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.77 | 274 | 604 | 0.454 | 0.0000397 | 6636 |
| Missense (PolyPhen) | 77 | 252.76 | 0.30463 | 2700 | ||
| Synonymous | 0.0747 | 246 | 248 | 0.994 | 0.0000172 | 2080 |
| Loss of Function | 4.37 | 16 | 49.1 | 0.326 | 0.00000275 | 548 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000060 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: 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, providing the energy for active transport of various nutrients.;
- Disease
- DISEASE: Migraine, familial hemiplegic, 2 (FHM2) [MIM:602481]: A subtype of migraine with aura associated with hemiparesis in some families. Migraine is a disabling symptom complex of periodic headaches, usually temporal and unilateral. Headaches are often accompanied by irritability, nausea, vomiting and photophobia, preceded by constriction of the cranial arteries. Migraine with aura is characterized by recurrent attacks of reversible neurological symptoms (aura) that precede or accompany the headache. Aura may include a combination of sensory disturbances, such as blurred vision, hallucinations, vertigo, numbness and difficulty in concentrating and speaking. {ECO:0000269|PubMed:12539047, ECO:0000269|PubMed:12953268, ECO:0000269|PubMed:21352219, ECO:0000269|PubMed:23838748, ECO:0000269|PubMed:23918834}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alternating hemiplegia of childhood 1 (AHC1) [MIM:104290]: A rare syndrome of episodic hemi- or quadriplegia lasting minutes to days. Most cases are accompanied by dystonic posturing, choreoathetoid movements, nystagmus, other ocular motor abnormalities, autonomic disturbances, and progressive cognitive impairment. It is typically distinguished from familial hemiplegic migraine by infantile onset and high prevalence of associated neurological deficits that become increasingly obvious with age. {ECO:0000269|PubMed:15174025}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.229
Intolerance Scores
- LoFtool
- 0.105
- RVIS EVS
- -1.37
- RVIS percentile EVS
- 4.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.280
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |