SNAP25

Chr 20AD

synaptosome associated protein 25

Also known as: CMS18, DEE117, RIC-4, RIC4, SEC9, SNAP, SNAP-25, SUP

NCBI Gene: 6616 ENSG00000132639 UniProt: P60880 OMIM: 600322

The protein contributes two of the four helices required for the t-SNARE complex that mediates synaptic vesicle docking and fusion, thereby regulating neurotransmitter release at presynaptic terminals. Mutations cause developmental and epileptic encephalopathy 117 through an autosomal dominant inheritance pattern. The high pLI score (0.99) and low LOEUF score (0.23) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 117MIM #616330

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · genetic developmental and epileptic encephalopathy · AD · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

150

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF*

Mechanism· G2P

📖

GeneReview available — SNAP25

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.987

Z-score 3.35

OE 0.00 (0.00–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.96Z-score

OE missense 0.27 (0.21–0.36)

36 obs / 131.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.23)

0≤0.351.4

Missense OE?0.27 (0.21–0.36)

0≤0.61.4

Synonymous OE?0.62

0≤1.21.6

LoF obs/exp: 0 / 13.0Missense obs/exp: 36 / 131.3Syn Z: 1.93

Background carrier burden — how many people carry a rare variant somewhere in SNAP25?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 950

163 rare PASS variants

Rare truncating (LoF)

1 in 14,000

10 rare PASS variants

Rare synonymous (reference)

1 in 790

80 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SNAP25. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 930	1 in 25,000
South Asian	~43k	1 in 400	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 1,900	≈ 1 in 27,000
European (Finnish)	~27k	1 in 1,800	≈ 1 in 13,000
Admixed American	~22k	1 in 720	none seen
African / African American	~21k	1 in 1,000	1 in 3,700
East Asian	~20k	1 in 1,100	1 in 1,000
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	≈ 1 in 960	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 6 of 7 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 7.? see exons ↓