VPS37C

Chr 11

VPS37C subunit of ESCRT-I

NCBI Gene: 55048 ENSG00000167987 UniProt: A5D8V6

VPS37C encodes a subunit of the ESCRT-I complex, which sorts ubiquitinated transmembrane proteins into multivesicular bodies and regulates vesicular trafficking. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy with seizures, developmental delay, and neurodegeneration. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, UniProt

VPS37C is a subunit of ESCRT-I (endosomal sorting complex required for transport I), a complex in the class E vacuolar protein sorting (VPS) pathway required for sorting ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies (Eastman et al., 2005 [PubMed 15509564]).[supplied by OMIM, Mar 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.038

Z-score 1.89

OE 0.38 (0.18–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.88–1.14)

167 obs / 166.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.38 (0.18–0.86)

0≤0.351.4

Missense OE?1.00 (0.88–1.14)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 4 / 10.6Missense obs/exp: 167 / 166.5Syn Z: 0.33

Background carrier burden — how many people carry a rare variant somewhere in VPS37C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

516 rare PASS variants

Rare truncating (LoF)

1 in 1,300

75 rare PASS variants

Rare synonymous (reference)

1 in 210

218 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VPS37C. 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 120	1 in 1,800
South Asian	~43k	1 in 68	1 in 470
Remaining (unassigned)	~30k	1 in 78	1 in 980
European (Finnish)	~27k	1 in 300	none seen
Admixed American	~22k	1 in 72	1 in 1,600
African / African American	~21k	1 in 69	1 in 3,200
East Asian	~20k	1 in 69	1 in 950
Ashkenazi Jewish	~13k	1 in 760	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 110	≈ 1 in 960

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 4.? see exons ↓