VAMP1

Chr 12ARAD

vesicle associated membrane protein 1

Also known as: CMS25, SAX1, SPAX1, SYB1, VAMP-1

NCBI Gene: 6843 ENSG00000139190 UniProt: P23763 OMIM: 185880

The VAMP1 protein is a key component of the synaptic vesicle docking and fusion machinery at presynaptic nerve terminals, working alongside syntaxins and SNAP25 to enable neurotransmitter release. Mutations cause either autosomal dominant spastic ataxia 1 or autosomal recessive congenital myasthenic syndrome, affecting the central nervous system and neuromuscular junction respectively. The gene shows tolerance to loss-of-function variation (pLI 0.004, LOEUF 1.145), suggesting different pathogenic mechanisms may underlie these distinct clinical presentations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Synapotobrevins, syntaxins, and the 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. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 1.152 OMIM phenotypes

Clinical Summary— VAMP1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 52 VUS of 148 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — VAMP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.004

Z-score 1.28

OE 0.54 (0.28–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.23Z-score

OE missense 0.57 (0.44–0.75)

38 obs / 66.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.28–1.15)

0≤0.351.4

Missense OE?0.57 (0.44–0.75)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 5 / 9.2Missense obs/exp: 38 / 66.3Syn Z: 0.47

This gene — mechanism propensity

0.86top 5%

GOF

0.7125th %ile

LOF

0.2289th %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

LOF1 literature citation · 86% of P/LP variants are LoF

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

DNBased on the finding of homozygous loss-of-function VAMP1 mutations in patients with autosomal recessive presynaptic congenital myasthenic syndrome-25 (CMS25; 618323) who inherited the mutations from unaffected heterozygous carriers, Monies et al. (2017) suggested that a dominant-negative effect, ra1

LOFConsequently, we predict that the mutation in patients leads to alternative splicing with the formation of an abnormal inactive isoform in neurons and subsequently results in haploinsufficiency.2

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

References

ClinVar Variant Classifications

148 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic7

VUS52

Likely Benign51

Benign16

Conflicting4

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	6	0	1	0	7
Likely Pathogenic	6	0	1	0	7
VUS	3	42	6	1	52
Likely Benign	1	4	29	17	51
Benign	0	0	15	1	16
Conflicting	—				4
Total	16	46	52	19	137

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

View in ClinVar →

46 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap VAMP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →