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

The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Synaptobrevins/VAMPs, syntaxins, and the 25-kD synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. This gene is thought to participate in neurotransmitter release at a step between docking and fusion. The protein forms a stable complex with syntaxin, synaptosomal-associated protein, 25 kD, and synaptotagmin. It also forms a distinct complex with synaptophysin. It is a likely candidate gene for familial infantile myasthenia (FIMG) because of its map location and because it encodes a synaptic vesicle protein of the type that has been implicated in the pathogenesis of FIMG. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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

14 unique Pathogenic / Likely Pathogenic· 28 VUS of 58 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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 OE?0.00 (0.00–0.42)

0≤0.351.4

Missense OE?0.52 (0.40–0.69)

0≤0.61.4

Synonymous OE?1.30

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

This gene — mechanism propensity

0.77top 25%

GOF

0.7126th %ile

LOF

0.4233th %ile

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

LOF36% of P/LP variants are LoF · LOEUF 0.42

GOFprediction 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.

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.1

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

References

1.PMID 30373833 ↗

ClinVar Variant Classifications

58 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic6

VUS28

Likely Benign9

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	6	0	0	8
Likely Pathogenic	3	3	0	0	6
VUS	3	24	1	0	28
Likely Benign	0	1	3	5	9
Benign	0	0	1	0	1
Conflicting	—				1
Total	8	34	5	5	53

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap VAMP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →