ATP6AP1

Chr XXLR

ATPase H+ transporting accessory protein 1

Also known as: 16A, ATP6IP1, ATP6S1, Ac45, CF2, VATPS1, XAP-3, XAP3

NCBI Gene: 537ENSG00000071553UniProt: Q15904

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]

Primary Disease Associations & Inheritance

Immunodeficiency 47MIM #300972
XLR
377
ClinVar variants
123
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ATP6AP1
🧬
Gene-Disease Validity (ClinGen)
congenital disorder of glycosylation type II · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
123 Pathogenic / Likely Pathogenic· 115 VUS of 377 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 0.991
Z-score 3.47
OE 0.00 (0.00–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.53Z-score
OE missense 0.68 (0.59–0.79)
127 obs / 185.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.59–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 0 / 14.1Missense obs/exp: 127 / 185.7Syn Z: 0.22

ClinVar Variant Classifications

377 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic114
Likely Pathogenic9
VUS115
Likely Benign93
Benign33
Conflicting13
114
Pathogenic
9
Likely Pathogenic
115
VUS
93
Likely Benign
33
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
112
0
114
Likely Pathogenic
0
2
7
0
9
VUS
2
78
33
2
115
Likely Benign
0
9
36
48
93
Benign
0
8
16
9
33
Conflicting
—13
Total29920459377

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ATP6AP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Immunodeficiency 47

MIM #300972

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
Ma T et al.·Nature
2022
Expanding the phenotype of ATP6AP1 deficiency.
Barua S et al.·Cold Spring Harb Mol Case Stud
2022
Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.
Morales-Romero B et al.·Mol Genet Metab
2024Case report
ATP6AP1 as a potential prognostic biomarker in CRC by comprehensive analysis and verification.
Zhang S et al.·Sci Rep
2024
Prenatal and postnatal phenotype of a pathologic variant in the ATP6AP1 gene.
Tvina A et al.·Eur J Med Genet
2020Case report
Clinical Presentation of a Patient with a Congenital Disorder of Glycosylation, Type IIs (ATP6AP1), and Liver Transplantation.
Semenova N et al.·Int J Mol Sci
2023Case report
Severe phenotype of ATP6AP1-CDG in two siblings with a novel mutation leading to a differential tissue-specific ATP6AP1 protein pattern, cellular oxidative stress and hepatic copper accumulation.
Ondruskova N et al.·J Inherit Metab Dis
2020Case report
Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.
Alharbi H et al.·J Inherit Metab Dis
2023Cohort
Evaluation of PEN2-ATP6AP1 axis as an antiparasitic target for metformin based on phylogeny analysis and molecular docking.
Liu C et al.·Mol Biochem Parasitol
2023
m6A related metabolic genes in breast cancer and their relationship with prognosis.
Tao Y et al.·Int Immunopharmacol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SSR4 Promote Gastric Cancer Progression by Regulating Mitochondrial Oxidative Phosphorylation via NDUFB11 and ATP6AP1.
Li A et al.·Mol Carcinog
2025
Congenital Disorder of Glycosylation Following ATP6AP1 Deficiency With Normal Liver Function: A Case Report.
Jabbaripour Sarmadian A et al.·Clin Case Rep
2025🔓 Open AccessCase report
ATP6AP1 drives pyroptosis-mediated immune evasion in hepatocellular carcinoma: a machine learning-guided therapeutic target.
Tang L et al.·Discov Oncol
2025🔓 Open Access
ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
Yan Z et al.·Cell Death Dis
2025🔓 Open Access
Lysosomal gene ATP6AP1 promotes doxorubicin resistance via up-regulating autophagic flux in breast cancer.
Fei Y et al.·Cancer Cell Int
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools