ATP6AP1

protein-coding

ATPase H+ transporting accessory protein 1

Gene summary

This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development. [provided by RefSeq, Aug 2013]

Previous symbols:

ATP6S1
ATP6IP1

MANE transcript

NM_001183.6

Inheritance

ClinVar variants

P:10U:183B:117

Top phenotype

Immunodeficiency 47

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:154,428,633-154,436,516

External References & Databases

Ensembl (ENSG00000071553)

Transcript & Mutation Effects

hg38 • Region Span ~7.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 47LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010504

Submitter: Illumina

immunodeficiency 47STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010504

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 47STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010504

Submitter: PanelApp Australia

immunodeficiency 47MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010504

Submitter: Ambry Genetics

congenital disorder of glycosylation type IIDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0005501

Submitter: ClinGen

*ATP6AP1* was first reported in relation to ATP6AP1-CDG (also known as Immunodeficiency 47, MIM#300972) in 2016 (Jansen EJ, et al., 2016, PMID: 27231034). ATP6AP1 codes for an accessory subunit of a V‐ATPase, which normally pumps cytosolic protons into the lumen of endocytic and secretory organelles and thus maintains the acidic pH to ensure their correct function. Hemizygous males typically present with hepatic dysfunction (ranging from increased transaminases to cholestasis, liver cirrhosis, and end stage liver failure), and immunodeficiency (frequent infections, leukopenia and low immunoglobulin levels). Hematological and neurological features are also common. Patients exhibit abnormal N-glycosylation and often abnormal 0-glycosylation patterns. Other features reported include sensorineural hearing loss, renal dysfunction, pancreatic insufficiency, and lipid and amino acid profile abnormalities, low serum copper and ceruloplasmin. Eleven missense and one nonsense variant have been reported in 19 male probands, and 12 additional male family members, from 10 publications, were curated (Jansen et al, 2016, PMID: 27231034; Witters et al, 2018, PMID: 29192153; Dimitrov et al, 2018, PMID: 29396028; Tvina et al, 2020; PMID: 32058063, Ondruskova et al, 2020, PMID: 32216104; Yang et al, 2021, PMID: 34621841; Barua et al, 2022, PMID: 35732497; Alharbi et al, 2023, PMID: 35732497; Dang et al, 2023, PMID: 36719165; Semenova et al, 2023; PMID: 37108612). The mechanism of pathogenicity appears to be loss of function. All genotyped patients were hemizygous males; where the inheritance pattern is known 6 probands had a de novo variant and 13 had a maternally inherited variant. The ATP6AP1:c.1036G>A (p.Glu346Lys) variant is a recurrent de novo variant, and is inherited in some cases (Jansen et al, 2016, PMID: 27231034; Yang et al, 2021, PMID: 34621841; Alharbi et al, 2023, PMID: 35732497; Dang et al, 2023, PMID: 36719165). This gene-disease association is supported by experimental evidence showing that the function of ATP6AP1 is consistent with disease phenotypes, and that ATP6AP1 interacts with other proteins associated with CDG (Supek et al, 1994, PMID: 7929063; Wang et al, 2020, PMID: 33065002; Huttlin et al, 2017, PMID: 28514442). Specifically, ATP6AP1 (also known as Ac45) has been shown to act as a central hub for bringing the subunits of v-ATPase together for assembly into the complex (PMID: 33065002). Other genes encoding subunits of v-ATPase have been associated with CDG and are known to impact assembly or structure of the complex (Van Damme). A knock-out and conditional knock-out mouse model result in embryonic lethality (Schoonderwoert et al, 2002 PMID: 11989824; Qin et al, 2011, PMID: 22087256). In summary, there is definitive evidence to support the relationship between *ATP6AP1* and ATP6AP1-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen CDG GCEP on the meeting date May 15, 2024 (SOP v10).

Clinical Genomic Database (CGD)

Immunodeficiency 47XL

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Gastrointestinal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Among other features, individuals may have infantile-onset severe infections (and hypogammaglobulinemia) and awareness may allow preventive measures and early and aggressive treatment of infections

Refs: 27231034; 29396028; 32058063; 32216104

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6AP1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 293

not specifiedTotal: 38

Immunodeficiency 47Total: 30

Inborn genetic diseasesTotal: 23

ATP6AP1-related disorderTotal: 12

Decreased total neutrophil countTotal: 1

ALG2-congenital disorder of glycosylationTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001183.6. 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 clinvar	78 clinvar	6 clinvar	100
missense	4 clinvar	5 clinvar	141 clinvar	22 clinvar	11 clinvar	183
nonsense			6 clinvar			6
start loss			2 clinvar			2
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			18 clinvar			18
Total	5	5	183	100	17	310

Highest pathogenic variant AF is 0.000004957817

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001183.6	RefSeq	NP_001174.2	10	MANE Select
ENST00000369762.7	Ensembl	ENSP00000358777.2	10	MANE Select
ENST00000422890.5	Ensembl	ENSP00000398511.1	6	Standard
ENST00000429585.5	Ensembl	ENSP00000408470.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atp6ap1b	Danio rerio	Structure: ciliated olfactory receptor neuron Quality: decreased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

atp6ap1b

Danio rerio

Structure: ciliated olfactory receptor neuron

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)

Biological Process

cellular iron ion homeostasis
insulin receptor signaling pathway
ATP hydrolysis coupled proton transport
regulation of cellular pH
transferrin transport

Molecular Function

transporter activity
ATP binding
Rab GTPase binding
proton-transporting ATP synthase activity, rotational mechanism
proton-transporting ATPase activity, rotational mechanism

Cellular Component

endoplasmic reticulum membrane
endosome membrane
integral component of membrane
proton-transporting two-sector ATPase complex
endoplasmic reticulum-Golgi intermediate compartment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369762
Coding exons: 10
Length: 7885
Individuals with no LoFs: 123422
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 123423
p: 0.00000405

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.53	127	186	0.684	0.0000151	3019
Missense (PolyPhen)		44	79.593	0.55282		1264
Synonymous	0.221	80	82.5	0.969	0.00000699	985
Loss of Function	3.47	0	14.1	0.00	9.75e-7	225

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000090	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles. Guides the V-type ATPase into specialized subcellular compartments, such as neuroendocrine regulated secretory vesicles or the ruffled border of the osteoclast, thereby regulating its activity. Involved in membrane trafficking and Ca(2+)-dependent membrane fusion. May play a role in the assembly of the V-type ATPase complex. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). {ECO:0000269|PubMed:28296633, ECO:0000305|PubMed:27231034}.;
Disease: DISEASE: Immunodeficiency 47 (IMD47) [MIM:300972]: A complex immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, defective glycosylation of serum proteins, and liver disease with neonatal jaundice and hepatosplenomegaly. Some patients may also have neurologic features, including seizures, mild intellectual disability, and behavioral abnormalities. Inheritance is X-linked recessive. {ECO:0000269|PubMed:27231034}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0867

Intolerance Scores

LoFtool: 0.0342
RVIS EVS: 0.44
RVIS percentile EVS: 77.7

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.841

Gene Damage Prediction

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