SYP

Chr X

synaptophysin

Also known as: MRX96, MRXSYP, XLID96

NCBI Gene: 6855 ENSG00000102003 UniProt: P08247

This gene encodes synaptophysin, an integral membrane protein of synaptic vesicles that regulates synaptic plasticity and directs targeting of synaptobrevin to intracellular compartments. Mutations cause X-linked intellectual developmental disorder with inheritance following an X-linked recessive pattern. The gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.39), indicating that complete loss of function is likely not tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an integral membrane protein of small synaptic vesicles in brain and endocrine cells. The protein also binds cholesterol and is thought to direct targeting of vesicle-associated membrane protein 2 (synaptobrevin) to intracellular compartments. Mutations in this gene are associated with an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.39

Clinical Summary— SYP

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Gene-Disease Validity (ClinGen)

non-syndromic X-linked intellectual disability · XLModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 66 VUS of 123 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.39LOEUF

pLI 0.915

Z-score 2.99

OE 0.08 (0.03–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.33Z-score

OE missense 0.67 (0.56–0.80)

87 obs / 129.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.39)

0≤0.351.4

Missense OE?0.67 (0.56–0.80)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 12.3Missense obs/exp: 87 / 129.8Syn Z: -1.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSYP-related intellectual developmental disorder, X-linkedLOFXLR

This gene — mechanism propensity

0.5082th %ile

GOF

0.6736th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF89% of P/LP variants are LoF · LOEUF 0.39

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic8

VUS66

Likely Benign16

Benign2

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	7	1	0	0	8
VUS	4	58	3	1	66
Likely Benign	0	6	2	8	16
Benign	0	0	0	2	2
Conflicting	—				2
Total	12	65	5	11	95

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

View in ClinVar →

69 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap SYP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →