STX8

Chr 17

syntaxin 8

ENSG00000170310 UniProt: Q9UNK0 OMIM: 604203

The encoded protein mediates vesicle trafficking in the early secretory pathway, including retrograde transport from cis-Golgi membranes to the endoplasmic reticulum and vesicle fusion during endosome maturation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive microcephaly. The gene shows minimal tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Vesicle trafficking protein that functions in the early secretory pathway, possibly by mediating retrograde transport from cis-Golgi membranes to the ER

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.25

Clinical Summary— STX8

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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?

1.25LOEUF

pLI 0.000

Z-score 0.77

OE 0.80 (0.53–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.54Z-score

OE missense 1.13 (0.99–1.30)

148 obs / 130.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.80 (0.53–1.25)

0≤0.351.4

Missense OE?1.13 (0.99–1.30)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 14 / 17.5Missense obs/exp: 148 / 130.5Syn Z: 0.90

This gene — mechanism propensity

0.78top 25%

GOF

0.75top 25%

LOF

0.2484th %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.