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: Q9H270

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 Vps11 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Primary Disease Associations & Inheritance

?Dystonia 32MIM #619637
AR
Leukodystrophy, hypomyelinating, 12MIM #616683
AR
583
ClinVar variants
12
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VPS11
🧬
Gene-Disease Validity (ClinGen)
VPS11-related neurological disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 134 VUS of 583 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.24–0.54)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.66–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 17 / 47.4Missense obs/exp: 384 / 533.6Syn Z: -0.78

ClinVar Variant Classifications

583 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic1
VUS134
Likely Benign399
Benign35
Conflicting3
11
Pathogenic
1
Likely Pathogenic
134
VUS
399
Likely Benign
35
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
10
0
11
Likely Pathogenic
0
0
1
0
1
VUS
2
115
15
2
134
Likely Benign
1
10
136
252
399
Benign
3
8
12
12
35
Conflicting
—3
Total6134174266583

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Dystonia 32

MIM #619637

Molecular basis of disorder known

Autosomal recessive

Leukodystrophy, hypomyelinating, 12

MIM #616683

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — VPS11
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy.
Stouth DW et al.·Autophagy
2024
ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota.
Kim S et al.·Autophagy
2021
Targeting VPS18 hampers retromer trafficking of PD-L1 and augments immunotherapy.
Dong T et al.·Sci Adv
2024
The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.
Li L et al.·FEBS J
2024
A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia.
Monfrini E et al.·Ann Neurol
2021
A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.
Zhang J et al.·PLoS Genet
2016Case report
Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.
Goldstein O et al.·Mol Genet Metab
2023
Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis.
Mulligan MK et al.·Proc Natl Acad Sci U S A
2006Meta-analysis
Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients.
Edvardson S et al.·J Med Genet
2015Case report
The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement.
Hörtnagel K et al.·J Inherit Metab Dis
2016Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools