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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 1.152 OMIM phenotypes

Clinical Summary— VAMP1

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Population Constraint (gnomAD)

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

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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 OE0.54 (0.28–1.15)

0≤0.351.4

Missense OE0.57 (0.44–0.75)

0≤0.61.4

Synonymous OE0.87

0≤1.21.6

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

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

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, raPMID:28600779

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.PMID:22958904

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