VPS11

Chr 11AR

VPS11 core subunit of CORVET and HOPS complexes

Also known as: DYT32, END1, HLD12, HLD12; DYT32, PEP5, RNF108, hVPS11

NCBI Gene: 55823ENSG00000160695UniProt: Q9H270OMIM: 608549

This protein functions as a core component of endosomal tethering complexes that regulate vesicle trafficking to lysosomes, mediating fusion of endosomes and autophagosomes with lysosomes. Biallelic mutations cause autosomal recessive leukodystrophy with hypomyelination and dystonia, affecting the central nervous system through disrupted lysosomal function. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.538), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 0.542 OMIM phenotypes
Clinical Summary— VPS11
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Gene-Disease Validity (ClinGen)
VPS11-related neurological disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
3 unique Pathogenic / Likely Pathogenic· 43 VUS of 400 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.54LOEUF
pLI 0.000
Z-score 4.09
OE 0.36 (0.24–0.54)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.30Z-score
OE missense 0.72 (0.66–0.78)
384 obs / 533.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.36 (0.24–0.54)
0≤0.351.4
Missense OE0.72 (0.66–0.78)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 17 / 47.4Missense obs/exp: 384 / 533.6Syn Z: -0.78
DN
0.6648th %ile
GOF
0.5661th %ile
LOF
0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
VUS43
Likely Benign330
Benign7
3
Pathogenic
43
VUS
330
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
3
0
3
Likely Pathogenic
0
0
0
0
0
VUS
2
38
3
0
43
Likely Benign
1
4
119
206
330
Benign
0
2
4
1
7
Total344129207383

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

View in ClinVar →

Protein Context — Lollipop Plot

VPS11 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients