ATP1A3

ATPase Na+/K+ transporting subunit alpha 3, the group of ATPase Na+/K+ transporting subunits

Basic information

Region (hg38): 19:41966582-41997497

Previous symbols: [ "DYT12" ]

Links

ENSG00000105409 ∙ NCBI:478 ∙ OMIM:182350 ∙ HGNC:801 ∙ Uniprot:P13637 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• alternating hemiplegia of childhood 2 (Strong), mode of inheritance: AD
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (Strong), mode of inheritance: AD
• dystonia 12 (Strong), mode of inheritance: AD
• alternating hemiplegia of childhood 2 (Definitive), mode of inheritance: AD
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (Definitive), mode of inheritance: AD
• dystonia 12 (Moderate), mode of inheritance: AD
• alternating hemiplegia of childhood (Supportive), mode of inheritance: AD
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (Supportive), mode of inheritance: AD
• dystonia 12 (Supportive), mode of inheritance: AD
• encephalopathy, acute, infection-induced (Moderate), mode of inheritance: AD
• ATP1A3-associated neurological disorder (Definitive), mode of inheritance: AD
• developmental and epileptic encephalopathy 99 (Strong), mode of inheritance: AD
• alternating hemiplegia of childhood 1 (Strong), mode of inheritance: AD
• alternating hemiplegia of childhood 2 (Strong), mode of inheritance: AD
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (Strong), mode of inheritance: AD
• dystonia 12 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy 99 (Strong), mode of inheritance: AD
• ATP1A3-associated neurological disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alternating hemiplegia of childhood 2; Dystonia 12; Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome	AD	Cardiovascular; Neurologic	In Alternating hemiplegia of childhood 2, medical treatment with calcium channel blockers has been described as beneficial (though not curative) for treatment of the hemiplegic attacks in the majority of individuals patients; Individuals with ATP1A3-related disorders have been described with arrhthymias, and awareness may allow surveillance and management (eg, with ICD or pacemaker placement); In Dystonia 12, reports indicate limited efficacy of levodopa treatment	Audiologic/Otolaryngologic; Cardiovascular; Neurologic; Ophthalmologic	8733056; 15260953; 17282997; 19652145; 20558373; 22842232; 22850527; 22857851; 22924536; 23409136; 24468074; 24842602; 25056583; 32913013; 33880529

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP1A3 gene.

• Dystonia 12 (51 variants)
• not provided (15 variants)
• Alternating hemiplegia of childhood 2 (15 variants)
• Inborn genetic diseases (5 variants)
• ATP1A3-related disorder (3 variants)
• Developmental and epileptic encephalopathy 99 (3 variants)
• Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;Alternating hemiplegia of childhood 2;Dystonia 12 (3 variants)
• Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (2 variants)
• Seizure (2 variants)
• not specified (1 variants)
• Epilepsy;Hemiplegia (1 variants)
• Ventriculomegaly;Abnormal earlobe morphology;Depressed nasal bridge;Seizure;Epicanthus (1 variants)
• Dystonia 12;Alternating hemiplegia of childhood 2 (1 variants)
• Oculogyric crisis;Hemiplegia;Global developmental delay (1 variants)
• ATP1A3-associated neurological disorder (1 variants)
• Oculogyric crisis;Tetraparesis;Dystonic disorder (1 variants)
• Dyskinesia;Neurodevelopmental delay;Dystonic disorder;Seizure (1 variants)
• Dystonia 12;Alternating hemiplegia of childhood 2;Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP1A3 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			13	293	11	317
missense	39	61	306	8	1	415
nonsense	6		2			8
start loss						0
frameshift	4	3	1			8
inframe indel	4	5	8			17
splice donor/acceptor (+/-2bp)	4	12	3			19
splice region			27	43	2	72
non coding			18	155	31	204
Total	57	81	351	456	43

Variants in ATP1A3

This is a list of pathogenic ClinVar variants found in the ATP1A3 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-41966622-C-T		Dystonia 12 • Alternating hemiplegia of childhood 2 • Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome • Developmental and epileptic encephalopathy 99	Benign/Likely benign (Feb 01, 2023)
19-41966638-C-T			Likely benign (Dec 15, 2020)
19-41966639-G-A		Alternating hemiplegia of childhood 2 • Dystonia 12	Uncertain significance (Jan 13, 2018)
19-41966641-G-A			Benign (Dec 13, 2020)
19-41966657-A-T		Dystonia 12 • Alternating hemiplegia of childhood 2	Uncertain significance (Jan 13, 2018)
19-41966690-G-A		Alternating hemiplegia of childhood 2 • Dystonia 12 • Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome • Developmental and epileptic encephalopathy 99	Benign (Dec 05, 2021)
19-41966701-A-G		Dystonia 12 • Alternating hemiplegia of childhood 2	Benign (Jan 13, 2018)
19-41966731-A-G		Alternating hemiplegia of childhood 2 • Dystonia 12	Uncertain significance (Jan 12, 2018)
19-41966810-T-G			Benign (Aug 07, 2018)
19-41966831-A-G		Dystonia 12 • Alternating hemiplegia of childhood 2 • Developmental and epileptic encephalopathy 99 • Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	Benign/Likely benign (Dec 05, 2021)
19-41966838-G-C		Dystonia 12 • Alternating hemiplegia of childhood 2	Uncertain significance (Jan 13, 2018)
19-41966865-T-C			Likely benign (Sep 23, 2020)
19-41966898-G-C		Alternating hemiplegia of childhood 2 • Dystonia 12 • Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome • not specified	Benign (Jul 15, 2024)
19-41966924-G-T		Dystonia 12 • Alternating hemiplegia of childhood 2	Uncertain significance (Apr 27, 2017)
19-41966937-T-G			Pathogenic (Jun 01, 2023)
19-41966938-C-CAGT		Dystonia 12	Pathogenic (Jul 01, 2009)
19-41966952-C-A		Dystonia 12	Uncertain significance (Mar 23, 2023)
19-41966952-C-T		Dystonia 12	Likely benign (Mar 06, 2023)
19-41966955-C-T		Dystonia 12	Likely benign (May 07, 2023)
19-41966957-C-T		Dystonia 12	Uncertain significance (Jan 22, 2024)
19-41966960-C-T		Dystonia 12	Uncertain significance (Aug 23, 2023)
19-41966965-C-T		Dystonia 12	Uncertain significance (Nov 17, 2023)
19-41966970-A-G		Dystonia 12	Likely benign (Feb 26, 2020)
19-41966976-A-G		Dystonia 12	Likely benign (Dec 12, 2023)
19-41966983-G-A		Dystonia 12	Likely benign (Jun 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP1A3	protein_coding	protein_coding	ENST00000545399	23	30916

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.24e-8	125738	0	2	125740	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.33	186	635	0.293	0.0000449	6745
Missense in Polyphen		73	365.49	0.19973		3855
Synonymous	-1.32	302	274	1.10	0.0000223	2066
Loss of Function	6.40	0	47.7	0.00	0.00000238	539

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
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 ions, providing the energy for active transport of various nutrients.
• Disease: DISEASE: Dystonia 12 (DYT12) [MIM:128235]: An autosomal dominant dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT12 patients develop dystonia and parkinsonism between 15 and 45 years of age. The disease is characterized by an unusually rapid evolution of signs and symptoms. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. {ECO:0000269|PubMed:15260953, ECO:0000269|PubMed:19351654, ECO:0000269|PubMed:19652145}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alternating hemiplegia of childhood 2 (AHC2) [MIM:614820]: 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:22842232, ECO:0000269|PubMed:22850527, ECO:0000269|PubMed:23409136, ECO:0000269|PubMed:24631656, ECO:0000269|PubMed:26993267}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) [MIM:601338]: An autosomal dominant neurologic disorder characterized by relapsing and partially remitting, early-onset cerebellar ataxia following a febrile illness. Other features include progressive optic atrophy and sensorineural hearing loss, generalized hypotonia, areflexia and pes cavus without evidence of a peripheral neuropathy on neurophysiological studies. {ECO:0000269|PubMed:24468074}. 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;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Ion channel transport;TCR;Purine metabolism;Ion homeostasis;Transport of small molecules;Cardiac conduction;Muscle contraction;Ion transport by P-type ATPases (Consensus)

Recessive Scores

• pRec: 0.184

Intolerance Scores

• loftool: 0.00296
• rvis_EVS: -1.53
• rvis_percentile_EVS: 3.37

Haploinsufficiency Scores

• pHI: 0.932
• hipred: Y
• hipred_score: 0.775
• ghis: 0.569

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.295

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atp1a3
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; hematopoietic system 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); 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); immune system phenotype; growth/size/body region 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); muscle phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: atp1a3b
• Affected structure: ventricular system
• Phenotype tag: abnormal
• Phenotype quality: dilated

Gene ontology

• Biological process: cellular sodium ion homeostasis;establishment or maintenance of transmembrane electrochemical gradient;ATP hydrolysis coupled proton transport;cellular potassium ion homeostasis;sodium ion export across plasma membrane;regulation of resting membrane potential;cellular response to steroid hormone stimulus;cell communication by electrical coupling involved in cardiac conduction;regulation of presynaptic membrane potential;response to glycoside;cellular response to amyloid-beta;neuron projection maintenance;potassium ion import across plasma membrane
• Cellular component: endoplasmic reticulum;Golgi apparatus;plasma membrane;sodium:potassium-exchanging ATPase complex;membrane;integral component of membrane;axon;neuronal cell body membrane;neuronal cell body;synapse;extracellular vesicle
• Molecular function: amyloid-beta binding;sodium:potassium-exchanging ATPase activity;ATP binding;metal ion binding;chaperone binding;ion antiporter activity involved in regulation of presynaptic membrane potential;steroid hormone binding