SYN1

Chr XX-linked

synapsin I

Also known as: EPILX, EPILX1, MRX50, SYN1a, SYN1b, SYNI

NCBI Gene: 6853 ENSG00000008056 UniProt: P17600

This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Epilepsy, X-linked 1, with variable learning disabilities and behavior disordersMIM #300491

X-linked

Intellectual developmental disorder, X-linked 50MIM #300115

X-linked

548

ClinVar variants

124

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

Clinical Summary— SYN1

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

124 Pathogenic / Likely Pathogenic· 232 VUS of 548 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.25LOEUF

pLI 0.992

Z-score 3.82

OE 0.05 (0.02–0.25)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.97Z-score

OE missense 0.47 (0.40–0.55)

116 obs / 247.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.05 (0.02–0.25)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.40–0.55)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.83

0≤1.21.6

LoF obs/exp: 1 / 18.9Missense obs/exp: 116 / 247.3Syn Z: 1.44