SCAMP5

Chr 15

secretory carrier membrane protein 5

NCBI Gene: 192683 ENSG00000198794 UniProt: Q8TAC9 OMIM: 613766

The SCAMP5 protein is required for calcium-dependent exocytosis of cytokines and cooperates with SNARE machinery in vesicle-mediated transport at the Golgi apparatus, plasma membrane, and recycling endosomes. Mutations cause autosomal recessive neurodevelopmental disorder with epilepsy, characterized by developmental delay, intellectual disability, and seizures typically beginning in infancy or early childhood. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.523), suggesting sensitivity to reduced protein levels.

OMIM ResearchSummary from RefSeq, UniProt

Involved in positive regulation of cytokine production; regulation of vesicle-mediated transport; and response to endoplasmic reticulum stress. Located in Golgi apparatus; plasma membrane; and recycling endosome membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.52

Clinical Summary— SCAMP5

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.651

Z-score 2.68

OE 0.17 (0.07–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.05Z-score

OE missense 0.52 (0.43–0.63)

75 obs / 144.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.52)

0≤0.351.4

Missense OE?0.52 (0.43–0.63)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 2 / 12.0Missense obs/exp: 75 / 144.2Syn Z: -0.86

This gene — mechanism propensity

0.74top 25%

GOF

0.79top 25%

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.