ATP1A1

ATPase Na+/K+ transporting subunit alpha 1, the group of ATPase Na+/K+ transporting subunits

Basic information

Region (hg38): 1:116372668-116410261

Links

ENSG00000163399 ∙ NCBI:476 ∙ OMIM:182310 ∙ HGNC:799 ∙ Uniprot:P05023 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• charcot-marie-tooth disease, axonal, type 2DD (Supportive), mode of inheritance: AD
• charcot-marie-tooth disease, axonal, type 2DD (Strong), mode of inheritance: AD
• hypomagnesemia, seizures, and intellectual disability 2 (Strong), mode of inheritance: AD
• charcot-marie-tooth disease, axonal, type 2DD (Moderate), mode of inheritance: AD
• charcot-marie-tooth disease, axonal, type 2DD (Moderate), mode of inheritance: AD
• hypomagnesemia, seizures, and intellectual disability 2 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypomagnesemia, seizures, and impaired intellectual development 2	AD	Renal	The condition can include renal salt wasting, and awareness may allow prompt management (however, seizures have been noted to persist despite magnesium supplementation)	Neurologic; Renal	29499166; 30388404

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP1A1 gene.

• Charcot-marie-tooth disease, axonal, type 2DD (2 variants)
• Charcot-Marie-Tooth disease type 2A2 (2 variants)
• not provided (2 variants)
• Hypomagnesemia, seizures, and intellectual disability 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP1A1 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			4	218	11	233
missense	4	6	186	10	1	207
nonsense			4			4
start loss						0
frameshift		1	6			7
inframe indel			3			3
splice donor/acceptor (+/-2bp)			2			2
splice region			19	29	4	52
non coding			6	129	36	171
Total	4	7	211	357	48

Variants in ATP1A1

This is a list of pathogenic ClinVar variants found in the ATP1A1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-116373434-C-T			Benign (May 10, 2021)
1-116373519-A-C		Charcot-marie-tooth disease, axonal, type 2DD	Uncertain significance (Feb 02, 2022)
1-116373520-G-A			Likely benign (Nov 09, 2022)
1-116373521-G-C			Uncertain significance (May 28, 2022)
1-116373526-G-T		not specified	Conflicting classifications of pathogenicity (Jun 27, 2023)
1-116373531-T-G			Likely benign (May 30, 2023)
1-116373532-C-A			Likely benign (Feb 20, 2023)
1-116373534-G-A			Benign (Nov 24, 2023)
1-116373535-G-A			Likely benign (Sep 29, 2023)
1-116373542-C-T			Likely benign (Nov 11, 2023)
1-116374023-CT-C			Benign (May 10, 2021)
1-116374231-T-TG			Uncertain significance (Dec 25, 2023)
1-116374250-T-A		Hypomagnesemia, seizures, and intellectual disability 2	Uncertain significance (Oct 01, 2019)
1-116383811-G-A			Benign (May 11, 2021)
1-116383998-C-G			Likely benign (Mar 23, 2021)
1-116384003-T-C			Likely benign (Sep 24, 2022)
1-116384010-A-G			Likely benign (Sep 06, 2022)
1-116384014-G-A			Uncertain significance (Jul 10, 2023)
1-116384014-G-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 15, 2023)
1-116384015-T-C		Inborn genetic diseases	Uncertain significance (Oct 27, 2023)
1-116384019-A-T			Likely benign (Sep 28, 2022)
1-116384020-C-T		Inborn genetic diseases	Uncertain significance (Apr 08, 2023)
1-116384021-G-A			Uncertain significance (May 24, 2023)
1-116384021-G-T			Uncertain significance (Mar 01, 2023)
1-116384026-A-C			Uncertain significance (Jul 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP1A1	protein_coding	protein_coding	ENST00000537345	23	37594

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.72e-7	125739	0	9	125748	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.22	171	599	0.285	0.0000334	6730
Missense in Polyphen		28	234.31	0.1195		2625
Synonymous	-1.40	250	223	1.12	0.0000135	2019
Loss of Function	6.43	2	52.0	0.0384	0.00000269	593

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000867	0.0000867
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.000163	0.000163

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.
• 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);Diuretics Pathway, Pharmacodynamics;Antiarrhythmic Pathway, Pharmacodynamics;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;Preimplantation Embryo;Ion channel transport;TCR;Purine metabolism;Ion homeostasis;Transport of small molecules;Cardiac conduction;Muscle contraction;EGFR1;Ion transport by P-type ATPases;TSH (Consensus)

Recessive Scores

• pRec: 0.333

Intolerance Scores

• loftool: 0.00730
• rvis_EVS: -1
• rvis_percentile_EVS: 8.37

Haploinsufficiency Scores

• pHI: 0.701
• hipred: Y
• hipred_score: 0.825
• ghis: 0.551

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.825

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Atp1a1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms 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); 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); homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: atp1a1a.1
• Affected structure: neuroepithelial cell
• Phenotype tag: abnormal
• Phenotype quality: decreased width

Gene ontology

• Biological process: regulation of the force of heart contraction;regulation of sodium ion transport;cellular sodium ion homeostasis;regulation of blood pressure;establishment or maintenance of transmembrane electrochemical gradient;ATP hydrolysis coupled proton transport;dephosphorylation;cellular potassium ion homeostasis;negative regulation of glucocorticoid biosynthetic process;sodium ion export across plasma membrane;response to drug;negative regulation of heart contraction;positive regulation of heart contraction;positive regulation of striated muscle contraction;relaxation of cardiac muscle;membrane hyperpolarization;cellular response to mechanical stimulus;cellular response to steroid hormone stimulus;cardiac muscle cell action potential involved in contraction;regulation of cardiac muscle cell contraction;membrane repolarization;membrane repolarization during cardiac muscle cell action potential;cell communication by electrical coupling involved in cardiac conduction;response to glycoside;potassium ion import across plasma membrane
• Cellular component: endosome;endoplasmic reticulum;Golgi apparatus;plasma membrane;sodium:potassium-exchanging ATPase complex;caveola;postsynaptic density;intercalated disc;membrane;integral component of membrane;basolateral plasma membrane;apical plasma membrane;T-tubule;protein-containing complex;sarcolemma;melanosome;myelin sheath;extracellular exosome;extracellular vesicle
• Molecular function: sodium:potassium-exchanging ATPase activity;protein binding;ATP binding;phosphatase activity;protein kinase binding;protein domain specific binding;ankyrin binding;potassium ion binding;sodium ion binding;ADP binding;phosphatidylinositol 3-kinase binding;chaperone binding;steroid hormone binding