VPS36

Chr 13

vacuolar protein sorting 36 homolog

Also known as: C13orf9, CGI-145, EAP45

NCBI Gene: 51028 ENSG00000136100 UniProt: Q86VN1

This protein is a subunit of the ESCRT-II complex that sorts ubiquitinated membrane proteins for lysosomal degradation and forms multivesicular bodies during endocytosis. Mutations cause autosomal recessive early infantile epileptic encephalopathy, characterized by severe seizures and developmental delays beginning in infancy. The gene shows moderate constraint against loss-of-function variants, consistent with its role in essential cellular trafficking processes.

ResearchSummary from RefSeq, UniProt

This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A similar protein complex in rat is associated with RNA polymerase elongation factor II. [provided by RefSeq, Aug 2013]

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

0.50

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?

0.50LOEUF

pLI 0.046

Z-score 3.59

OE 0.28 (0.16–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.71Z-score

OE missense 0.67 (0.58–0.77)

138 obs / 207.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.16–0.50)

0≤0.351.4

Missense OE?0.67 (0.58–0.77)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 8 / 28.7Missense obs/exp: 138 / 207.4Syn Z: 1.18

Background carrier burden — how many people carry a rare variant somewhere in VPS36?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

369 rare PASS variants

Rare truncating (LoF)

1 in 2,600

61 rare PASS variants

Rare synonymous (reference)

1 in 280

146 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VPS36. 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 260	1 in 3,800
South Asian	~43k	1 in 240	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 340	1 in 3,800
European (Finnish)	~27k	1 in 3,000	none seen
Admixed American	~22k	1 in 290	1 in 1,000
African / African American	~21k	1 in 330	1 in 2,000
East Asian	~20k	1 in 140	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 390	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 160	≈ 1 in 2,900

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 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓