VPS18

Chr 15

VPS18 core subunit of CORVET and HOPS complexes

Also known as: PEP3

NCBI Gene: 57617 ENSG00000104142 UniProt: Q9P253

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps18 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. [provided by RefSeq, Jul 2008]

Research

ResearchGenerating clinical summary…

Clinical highlights

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

0.40

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.476

Z-score 4.38

OE 0.22 (0.13–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.63Z-score

OE missense 0.93 (0.86–0.99)

560 obs / 603.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.40)

0≤0.351.4

Missense OE?0.93 (0.86–0.99)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 8 / 36.6Missense obs/exp: 560 / 603.3Syn Z: -0.22

Background carrier burden — how many people carry a rare variant somewhere in VPS18?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

1,248 rare PASS variants

Rare truncating (LoF)

1 in 3,700

80 rare PASS variants

Rare synonymous (reference)

1 in 73

551 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VPS18. 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)	~556k	1 in 52	1 in 3,900
South Asian	~43k	1 in 42	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 48	1 in 6,000
European (Finnish)	~27k	1 in 160	1 in 2,600
Admixed American	~22k	1 in 52	1 in 2,800
African / African American	~21k	1 in 42	1 in 2,700
East Asian	~20k	1 in 50	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 350	1 in 2,600
Middle Eastern	~2,884	1 in 36	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 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓