VAPB

Chr 20AD

VAMP associated protein B and C

Also known as: ALS8, VAMP-B, VAP-B

NCBI Gene: 9217ENSG00000124164UniProt: O95292

The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 8MIM #608627
AD
Spinal muscular atrophy, late-onset, Finkel typeMIM #182980
AD
0
Active trials
8
Pathogenic / LP
39
ClinVar variants
48
Pubs (1 yr)
1.3
Missense Z
0.56
LOEUF
Clinical Summary— VAPB
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 8 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 9 VUS of 39 total submissions
📖
GeneReview available — VAPB
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.56LOEUF
pLI 0.581
Z-score 2.56
OE 0.18 (0.07–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.25Z-score
OE missense 0.70 (0.59–0.83)
94 obs / 135.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.18 (0.07–0.56)
0≤0.351.4
Missense OE0.70 (0.59–0.83)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 2 / 11.3Missense obs/exp: 94 / 135.0Syn Z: 0.68
DNLOF
DN
0.6455th %ile
GOF
0.5170th %ile
LOF
0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation
LOF1 literature citation

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.

Literature Evidence

DNOne such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions.PMID:25361581
LOFA mutant, aggregation-prone, form of VAPB (P56S) is linked to a dominantly inherited form of amyotrophic lateral sclerosis; however, it has been unclear whether its pathogenicity is due to toxic gain of function, to negative dominance, or simply to insufficient levels of the wild-type protein producPMID:30745341

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

39 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic2
VUS9
Likely Benign4
Benign12
Conflicting6
6
Pathogenic
2
Likely Pathogenic
9
VUS
4
Likely Benign
12
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
4
0
6
Likely Pathogenic
0
0
2
0
2
VUS
0
0
9
0
9
Likely Benign
0
1
3
0
4
Benign
0
0
12
0
12
Conflicting
—6
Total0330039

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

View in ClinVar →

VAPB · 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.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
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