VAMP2

Chr 17AD

vesicle associated membrane protein 2

Also known as: NEDHAHM, SYB2, VAMP-2

NCBI Gene: 6844 ENSG00000220205 UniProt: P63027 OMIM: 185881

The protein is a synaptic vesicle membrane protein that participates in neurotransmitter release by forming complexes with syntaxin, SNAP25, and synaptotagmin to facilitate docking and fusion of synaptic vesicles with the presynaptic membrane. Mutations cause autosomal dominant neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements. The pathogenic mechanism involves dominant-negative effects that disrupt normal synaptic vesicle fusion and neurotransmitter release.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.421 OMIM phenotype

Clinical Summary— VAMP2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 40 VUS of 89 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.42LOEUF

pLI 0.887

Z-score 2.47

OE 0.00 (0.00–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.41Z-score

OE missense 0.52 (0.40–0.69)

36 obs / 69.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.42)

0≤0.351.4

Missense OE0.52 (0.40–0.69)

0≤0.61.4

Synonymous OE1.30

0≤1.21.6

LoF obs/exp: 0 / 7.1Missense obs/exp: 36 / 69.0Syn Z: -1.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongVAMP2-related intellectual disabilityOTHERAD

0.77top 25%

GOF

0.7126th %ile

LOF

0.4233th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function 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

GOFprediction above median

LOF15% of P/LP variants are LoF · LOEUF 0.42

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

DNTransgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve.PMID:30373833

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.