VPS4B

Chr 18AD

vacuolar protein sorting 4 homolog B

Also known as: DTDP1B, MIG1, SKD1, SKD1B, VPS4-2

NCBI Gene: 9525ENSG00000119541UniProt: O75351

VPS4B encodes an ATPase that catalyzes the disassembly of ESCRT-III protein complexes during the late steps of endosomal multivesicular body formation, enabling proper intracellular protein trafficking and degradation of membrane proteins. Mutations cause dentin dysplasia type IB, a dental developmental disorder affecting tooth structure. This condition follows autosomal dominant inheritance.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

?Dentin dysplasia, type IBMIM #621440
AD
0
Active trials
5
Pubs (1 yr)
98
P/LP submissions
0%
P/LP missense
0.48
LOEUF
DN
Mechanism· predicted
Clinical Summary— VPS4B
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
95 unique Pathogenic / Likely Pathogenic· 44 VUS of 149 total submissions
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.48LOEUF
pLI 0.230
Z-score 3.50
OE 0.24 (0.13–0.48)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.41Z-score
OE missense 0.56 (0.49–0.65)
133 obs / 237.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.24 (0.13–0.48)
0≤0.351.4
Missense OE0.56 (0.49–0.65)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 6 / 24.8Missense obs/exp: 133 / 237.5Syn Z: 0.01
DN
0.76top 25%
GOF
0.6052th %ile
LOF
0.2871th %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

149 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic88
Likely Pathogenic7
VUS44
88
Pathogenic
7
Likely Pathogenic
44
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
88
0
88
Likely Pathogenic
0
0
7
0
7
VUS
0
38
6
0
44
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total0381010139

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

View in ClinVar →

Protein Context — Lollipop Plot

VPS4B · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 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