VAMP2

Chr 17AD

vesicle associated membrane protein 2

Also known as: NEDHAHM, SYB2, VAMP-2

NCBI Gene: 6844ENSG00000220205UniProt: P63027

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]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movementsMIM #618760
AD
84
ClinVar variants
33
Pathogenic / LP
0.89
pLI score
0
Active trials
Clinical Summary— VAMP2
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 40 VUS of 84 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.41Z-score
OE missense 0.52 (0.40–0.69)
36 obs / 69.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.40–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30
0≤1.21.6
LoF obs/exp: 0 / 7.1Missense obs/exp: 36 / 69.0Syn Z: -1.26

ClinVar Variant Classifications

84 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic6
VUS40
Likely Benign9
Benign1
Conflicting1
27
Pathogenic
6
Likely Pathogenic
40
VUS
9
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
21
0
27
Likely Pathogenic
2
3
1
0
6
VUS
2
23
15
0
40
Likely Benign
0
1
3
5
9
Benign
0
0
1
0
1
Conflicting
—1
Total53241584

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

View in ClinVar →

Protein Context — Lollipop Plot

VAMP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

VAMP2-related intellectual disability

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements

MIM #618760

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Anchored multiplex PCR for targeted next-generation sequencing.
Zheng Z et al.·Nat Med
2014
Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.
Burré J et al.·Science
2010
Phosphorylated tau interactome in the human Alzheimer's disease brain.
Drummond E et al.·Brain
2020
Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.
Liao P et al.·Transl Neurodegener
2022
SNAREs and developmental disorders.
Tang BL·J Cell Physiol
2021Review
Recent genetic advances in early-onset dystonia.
Steel D et al.·Curr Opin Neurol
2020Review
Influence of co-pathology on CSF and plasma synaptic markers SNAP25 and VAMP2 in Alzheimer's disease and Parkinson's disease.
Gaetani L et al.·Alzheimers Res Ther
2025
APOE4 triggers dysregulated synaptic vesicle release by disrupting SNARE complex assembly.
Chen F et al.·Cell Mol Life Sci
2025
Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.
Simmons RL et al.·Hum Mutat
2020
SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond.
Cupertino RB et al.·J Neural Transm (Vienna)
2016Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools