SNAPIN

Chr 1AR

SNAP associated protein

Also known as: BLOC1S7, BLOS7, BORCS3, NEDBAC, SNAPAP

NCBI Gene: 23557 ENSG00000143553 UniProt: O95295 OMIM: 607007

SNAPIN encodes a component of the BLOC-1 complex required for biogenesis of lysosome-related organelles and synaptic vesicle trafficking, and also participates in SNARE-mediated neurotransmitter release at synapses. Mutations cause autosomal recessive neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a coiled-coil-forming protein that associates with the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) complex of proteins and the BLOC-1 (biogenesis of lysosome-related organelles) complex. Biochemical studies have identified additional binding partners. As part of the SNARE complex, it is required for vesicle docking and fusion and regulates neurotransmitter release. The BLOC-1 complex is required for the biogenesis of specialized organelles such as melanosomes and platelet dense granules. Mutations in gene products that form the BLOC-1 complex have been identified in mouse strains that are models of Hermansky-Pudlak syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.441 OMIM phenotype

Clinical Summary— SNAPIN

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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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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 16 VUS of 23 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.44LOEUF

pLI 0.002

Z-score 0.77

OE 0.69 (0.36–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.88Z-score

OE missense 0.73 (0.59–0.90)

59 obs / 81.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.36–1.44)

0≤0.351.4

Missense OE?0.73 (0.59–0.90)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 7.2Missense obs/exp: 59 / 81.3Syn Z: -0.69

This gene — mechanism propensity

0.76top 25%

GOF

0.6932th %ile

LOF

0.3649th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative 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

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.

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

ClinVar Variant Classifications

23 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS16

Pathogenic

Likely Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	3	0	0	3
Likely Pathogenic	0	2	0	2
VUS	1	14	1	16
Likely Benign	0	0	0	0
Benign	0	0	0	0
Total	4	16	1	21

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

View in ClinVar →

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