ATP6AP1

Chr XXLR

ATPase H+ transporting accessory protein 1

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

NCBI Gene: 537 ENSG00000071553 UniProt: Q15904 OMIM: 300197

The protein is an accessory subunit of the vacuolar ATPase complex that acidifies intracellular organelles including neuroendocrine secretory vesicles and is involved in membrane trafficking and intracellular iron homeostasis. Mutations cause X-linked recessive immunodeficiency 47. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical consequences.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 47MIM #300972

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · congenital disorder of glycosylation type II · XL · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.21

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

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?

1.53Z-score

OE missense 0.68 (0.59–0.79)

127 obs / 185.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.21)

0≤0.351.4

Missense OE?0.68 (0.59–0.79)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 0 / 14.1Missense obs/exp: 127 / 185.7Syn Z: 0.22

Background carrier burden — how many people carry a rare variant somewhere in ATP6AP1?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

323 rare PASS variants

Rare truncating (LoF)

1 in 72,000

6 rare PASS variants

Rare synonymous (reference)

1 in 450

199 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATP6AP1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 190	1 in 62,000
South Asian	~36k	1 in 160	none seen
Remaining (unassigned)	~31k	1 in 180	≈ 1 in 31,000
European (Finnish)	~27k	1 in 590	none seen
Admixed American	~23k	1 in 150	none seen
African / African American	~21k	1 in 170	none seen
East Asian	~20k	1 in 250	none seen
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,758	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓