ATP4A

protein-coding

ATPase H+/K+ transporting subunit alpha, the group of ATPase H+/K+ transporting

Gene summary

The protein encoded by this gene belongs to a family of P-type cation-transporting ATPases. The gastric H+, K+-ATPase is a heterodimer consisting of a high molecular weight catalytic alpha subunit and a smaller but heavily glycosylated beta subunit. This enzyme is a proton pump that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for gastric acid secretion. This gene encodes a catalytic alpha subunit of the gastric H+, K+-ATPase. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000704.3

Inheritance

ClinVar variants

U:174B:59

Top phenotype

familial gastric type 1 neuroendocrine tumor

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr19:35,550,031-35,563,658

External References & Databases

Ensembl (ENSG00000105675)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial gastric type 1 neuroendocrine tumorSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018742

Submitter: Orphanet

gastric neuroendocrine neoplasmLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0003111

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP4A variants in ClinVar

2 Conditions Cataloged

not providedTotal: 145

not specifiedTotal: 141

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000704.3. 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			1 clinvar	32 clinvar	21 clinvar	54
missense			169 clinvar	5 clinvar	1 clinvar	175
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	174	37	22	233

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000704.3	RefSeq	NP_000695.2	22	MANE Select
ENST00000262623.4	Ensembl	ENSP00000262623.2	22	MANE Select
ENST00000592767.2	Ensembl	ENSP00000472323.2	2	Standard
ENST00001141237.1	Ensembl	ENSP00000803347.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric acid secretion - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)
Collecting duct acid secretion - Homo sapiens (human)
Proton Pump Inhibitor Pathway, Pharmacodynamics
Omeprazole Metabolism Pathway

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

Molecular Function

magnesium ion binding
sodium:potassium-exchanging ATPase activity
ATP binding
potassium:proton exchanging ATPase activity

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262623
Coding exons: 22
Length: 13616
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.87	455	663	0.686	0.0000420	6709
Missense (PolyPhen)		187	303.71	0.61572		3087
Synonymous	-0.798	306	289	1.06	0.0000205	2101
Loss of Function	2.98	26	48.3	0.538	0.00000224	534

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. Responsible for acid production in the stomach.;

Recessive Scores

pRec: 0.135

Intolerance Scores

LoFtool: 0.123
RVIS EVS: -0.97
RVIS percentile EVS: 8.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.251

Gene Damage Prediction

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