VPS50

Chr 7

VPS50 subunit of EARP/GARPII complex

Also known as: CCDC132, NEDMSC, VPS54L

NCBI Gene: 55610 ENSG00000004766 UniProt: Q96JG6

The VPS50 protein is a component of the EARP complex that mediates endocytic recycling by tethering the complex to recycling endosomes and promoting recycling of internalized receptors like transferrin receptor to the plasma membrane. Biallelic mutations cause a neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, reflecting involvement of the nervous system, brain development, and hepatic function. This condition follows autosomal recessive inheritance.

ResearchSummary from RefSeq, OMIM, UniProt

Enables SNARE binding activity. Acts upstream of or within endocytic recycling. Located in recycling endosome. Part of EARP complex. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

Clinical Summary— VPS50

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 89 VUS of 154 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.814

Z-score 5.63

OE 0.21 (0.13–0.33)

Highly constrained

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

Missense Constraint?

2.50Z-score

OE missense 0.68 (0.62–0.74)

325 obs / 479.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.21 (0.13–0.33)

0≤0.351.4

Missense OE?0.68 (0.62–0.74)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 12 / 58.4Missense obs/exp: 325 / 479.1Syn Z: -0.25

This gene — mechanism propensity

0.6357th %ile

GOF

0.6150th %ile

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF78% of P/LP variants are LoF · LOEUF 0.33

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

154 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic5

VUS89

Likely Benign9

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	1	0	4
Likely Pathogenic	5	0	0	0	5
VUS	2	87	0	0	89
Likely Benign	0	3	0	6	9
Benign	0	1	0	1	2
Total	9	92	1	7	109

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap VPS50 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →