VAPB

Chr 20AD

VAMP associated protein B and C

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

NCBI Gene: 9217 ENSG00000124164 UniProt: O95292 OMIM: 605704

VAPB encodes an endoplasmic reticulum-anchored protein that mediates contact sites between the ER and endosomes, participates in the unfolded protein response, and regulates cellular calcium homeostasis. Mutations cause late-onset motor neuron diseases including amyotrophic lateral sclerosis 8 and spinal muscular atrophy (Finkel type), with inheritance following an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.559).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.562 OMIM phenotypes

Clinical Summary— VAPB

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis type 8 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 234 VUS of 418 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — VAPB

Authoritative clinical overview · Recommended first read

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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 OE?0.18 (0.07–0.56)

0≤0.351.4

Missense OE?0.70 (0.59–0.83)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 2 / 11.3Missense obs/exp: 94 / 135.0Syn Z: 0.68

This gene — mechanism propensity

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.1

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 produc2

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

References

ClinVar Variant Classifications

418 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS234

Likely Benign109

Benign56

Conflicting14

Pathogenic

234

VUS

109

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	8	130	96	0	234
Likely Benign	0	6	68	35	109
Benign	0	0	53	3	56
Conflicting	—				14
Total	8	138	217	38	415

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap VAPB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →