ATP1A2

ATPase Na+/K+ transporting subunit alpha 2, the group of ATPase Na+/K+ transporting subunits

Basic information

Region (hg38): 1:160115758-160143591

Previous symbols: [ "MHP2" ]

Links

ENSG00000018625 ∙ NCBI:477 ∙ OMIM:182340 ∙ HGNC:800 ∙ Uniprot:P50993 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• migraine, familial hemiplegic, 2 (Strong), mode of inheritance: AD
• alternating hemiplegia of childhood 1 (Strong), mode of inheritance: AD
• alternating hemiplegia of childhood 1 (Limited), mode of inheritance: AD
• migraine, familial hemiplegic, 2 (Definitive), mode of inheritance: AD
• alternating hemiplegia of childhood (Supportive), mode of inheritance: AD
• familial or sporadic hemiplegic migraine (Supportive), mode of inheritance: AD
• fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (Moderate), mode of inheritance: AR
• alternating hemiplegia of childhood 1 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy 98 (Strong), mode of inheritance: AD
• migraine, familial hemiplegic, 2 (Strong), mode of inheritance: AD
• fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (Strong), mode of inheritance: AR
• hemiplegic migraine-developmental and epileptic encephalopathy spectrum (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic 2	AD	Neurologic; Pharmacogenomic	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	Craniofacial; Musculoskeletal; Neurologic	9579893; 12539047; 12953268; 14667076; 14636773; 14636773; 15159495; 15174025; 15210532; 15286158; 15459825; 15985592; 16437583; 16344534; 16538223; 17142831; 17473835; 18056581; 18028456; 18846413; 20301562; 20837964; 21352219; 22759692; 23203776; 23838748; 23918834; 30690204; 31608932; 33880529

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP1A2 gene.

• Familial hemiplegic migraine (803 variants)
• not provided (346 variants)
• Migraine, familial hemiplegic, 2 (189 variants)
• Alternating hemiplegia of childhood 1 (169 variants)
• not specified (118 variants)
• Inborn genetic diseases (109 variants)
• Developmental and epileptic encephalopathy 98 (77 variants)
• Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (75 variants)
• ATP1A2-related condition (14 variants)
• Alternating hemiplegia of childhood 1;Migraine, familial hemiplegic, 2 (9 variants)
• Alternating hemiplegia of childhood (9 variants)
• Migraine, familial hemiplegic, 2;Alternating hemiplegia of childhood 1 (5 variants)
• Alternating hemiplegia of childhood 1;Migraine, familial hemiplegic, 2;Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies;Developmental and epileptic encephalopathy 98 (4 variants)
• See cases (2 variants)
• Polymicrogyria (2 variants)
• Alternating hemiplegia of childhood 1;Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies;Developmental and epileptic encephalopathy 98;Migraine, familial hemiplegic, 2 (2 variants)
• Alternating hemiplegia of childhood;Migraine, familial hemiplegic, 2 (1 variants)
• Migraine, familial hemiplegic, 2;Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies;Developmental and epileptic encephalopathy 98;Alternating hemiplegia of childhood 1 (1 variants)
• Epilepsy (1 variants)
• Spastic ataxia (1 variants)
• ATP1A2-associated neurological disorder (1 variants)
• Migraine, familial basilar (1 variants)
• Hemiplegia (1 variants)
• Seizure (1 variants)
• Epileptic encephalopathy (1 variants)
• ATP1A2-RELATED DISORDERS (1 variants)
• Dysphasia;Hemiparesis;Headache (1 variants)
• Hydrops fetalis;Abnormality of neuronal migration;Arthrogryposis multiplex congenita;Epilepsy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP1A2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	205	8	218
missense	17	35	373	11		436
nonsense	6	4				10
start loss			1			1
frameshift	11	9				20
inframe indel	1	1	3			5
splice donor/acceptor (+/-2bp)	1	8	2			11
splice region		1	32	37	5	75
non coding			50	152	90	292
Total	36	57	434	368	98

Highest pathogenic variant AF is 0.0000263

Variants in ATP1A2

This is a list of pathogenic ClinVar variants found in the ATP1A2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-160115792-G-A		Migraine, familial hemiplegic, 2 • Alternating hemiplegia of childhood 1	Uncertain significance (Jan 13, 2018)
1-160115814-C-G		not specified • Migraine, familial hemiplegic, 2 • Alternating hemiplegia of childhood 1 • Developmental and epileptic encephalopathy 98 • Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies	Benign (Dec 05, 2021)
1-160115829-C-A		not specified	Likely benign (Jul 10, 2017)
1-160115831-C-G		not specified	Likely benign (Sep 19, 2017)
1-160115832-G-A		not specified	Likely benign (Jan 04, 2018)
1-160115848-C-G		not specified	Likely benign (Apr 25, 2013)
1-160115863-T-C		Familial hemiplegic migraine	Uncertain significance (Oct 09, 2020)
1-160115868-C-T		Familial hemiplegic migraine	Uncertain significance (Aug 15, 2022)
1-160115869-G-A		not specified • Familial hemiplegic migraine • Migraine, familial hemiplegic, 2	Conflicting classifications of pathogenicity (Jan 10, 2024)
1-160115871-G-A		Familial hemiplegic migraine	Uncertain significance (Feb 20, 2022)
1-160115874-G-A		Familial hemiplegic migraine	Likely pathogenic (Aug 16, 2023)
1-160115875-T-A		Migraine, familial hemiplegic, 2	Likely pathogenic (Mar 25, 2024)
1-160115876-G-A		Familial hemiplegic migraine	Uncertain significance (Aug 17, 2023)
1-160115879-T-C		Familial hemiplegic migraine	Uncertain significance (Apr 25, 2023)
1-160115882-C-T		Familial hemiplegic migraine	Likely benign (Mar 29, 2022)
1-160115883-C-T		Familial hemiplegic migraine	Likely benign (Jan 05, 2023)
1-160115884-C-T		Familial hemiplegic migraine	Likely benign (May 28, 2022)
1-160115888-AG-A		Familial hemiplegic migraine	Likely benign (Aug 18, 2023)
1-160115953-G-T			Likely benign (Aug 12, 2018)
1-160116078-A-C			Benign (Jun 14, 2018)
1-160116165-A-C			Benign (Jun 19, 2018)
1-160120669-T-G			Benign (Jul 07, 2018)
1-160120884-T-C		Alternating hemiplegia of childhood 1 • Migraine, familial hemiplegic, 2 • Developmental and epileptic encephalopathy 98 • Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies	Benign (Dec 05, 2021)
1-160120886-G-A		Familial hemiplegic migraine	Likely benign (Nov 22, 2022)
1-160120886-G-C		Familial hemiplegic migraine	Likely benign (Jan 17, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP1A2	protein_coding	protein_coding	ENST00000361216	23	27833

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000181	1.00	125720	0	28	125748	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.77	274	604	0.454	0.0000397	6636
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000121	0.000121
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000163	0.000163
Finnish	0.000142	0.000139
European (Non-Finnish)	0.000115	0.000114
Middle Eastern	0.000163	0.000163
South Asian	0.000165	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Carbohydrate digestion and absorption - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Proximal tubule bicarbonate reclamation - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Aldosterone-regulated sodium reabsorption - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Mineral absorption - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Levomethadyl Acetate Action Action Pathway;Polythiazide Action Pathway;Methyclothiazide Action Pathway;Bumetanide Action Pathway;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Spironolactone Action Pathway;Eplerenone Action Pathway;Triamterene Action Pathway;Amiloride Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Trehalose Degradation;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Ethacrynic Acid Action Pathway;Quinethazone Action Pathway;Bendroflumethiazide Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Nicotine Action Pathway;Chlorthalidone Action Pathway;Trichlormethiazide Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Iminoglycinuria;Lysinuric Protein Intolerance;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Muscle/Heart Contraction;Blue diaper syndrome;Lysinuric protein intolerance (LPI);Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Bupranolol Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Nebivolol Action Pathway;Cystinuria;Amlodipine Action Pathway;Verapamil Action Pathway;Indapamide Action Pathway;Furosemide Action Pathway;Torsemide Action Pathway;Hartnup Disorder;Glucose Transporter Defect (SGLT2);Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Kidney Function;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Glucose Transporter Defect (SGLT2);Carvedilol Action Pathway;Labetalol Action Pathway;Lactose Degradation;Lactose Intolerance;Metolazone Action Pathway;Hydrochlorothiazide Action Pathway;Cyclothiazide Action Pathway;Hydroflumethiazide Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Chlorothiazide Action Pathway;Dezocine Action Pathway;Synaptic Vesicle Pathway;Ion channel transport;Purine metabolism;Ion homeostasis;Transport of small molecules;Cardiac conduction;Muscle contraction;Ion transport by P-type ATPases (Consensus)

Recessive Scores

• pRec: 0.229

Intolerance Scores

• loftool: 0.105
• rvis_EVS: -1.37
• rvis_percentile_EVS: 4.43

Haploinsufficiency Scores

• pHI: 0.537
• hipred: Y
• hipred_score: 0.747
• ghis: 0.589

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.280

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Atp1a2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: atp1a2a
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: curved dorsal

Gene ontology

• 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;cellular sodium ion homeostasis;regulation of smooth muscle contraction;regulation of striated muscle contraction;regulation of blood pressure;adult locomotory behavior;visual learning;establishment or maintenance of transmembrane electrochemical gradient;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;ATP hydrolysis coupled proton transport;regulation of vasoconstriction;cellular potassium ion homeostasis;response to nicotine;sodium ion export across plasma membrane;locomotion;negative regulation of heart contraction;negative regulation of striated muscle contraction;ATP metabolic process;negative regulation of cytosolic calcium ion concentration;regulation of glutamate uptake involved in transmission of nerve impulse;regulation of synaptic transmission, glutamatergic;relaxation of cardiac muscle;cardiac muscle contraction;cellular response to mechanical stimulus;cellular response to steroid hormone stimulus;regulation of cardiac muscle cell contraction;membrane repolarization;membrane depolarization during cardiac muscle cell action potential;cell communication by electrical coupling involved in cardiac conduction;negative regulation of calcium ion transmembrane transport;negative regulation of calcium:sodium antiporter activity;response to glycoside;potassium ion import across plasma membrane
• Cellular component: cytoplasm;endosome;plasma membrane;sodium:potassium-exchanging ATPase complex;caveola;intercalated disc;membrane;T-tubule;dendritic spine;myelin sheath;extracellular vesicle
• Molecular function: sodium:potassium-exchanging ATPase activity;protein binding;ATP binding;drug binding;ATPase activity;potassium ion binding;sodium ion binding;chaperone binding;steroid hormone binding