SYNGAP1

Chr 6AD

synaptic Ras GTPase activating protein 1

Also known as: MRD5, RASA5, SYNGAP

NCBI Gene: 8831ENSG00000197283UniProt: Q96PV0OMIM: 603384

The protein negatively regulates Ras, Rap, and AMPA receptor trafficking to the postsynaptic membrane, controlling synaptic plasticity and neuronal homeostasis as part of the NMDA receptor complex. Mutations cause autosomal dominant intellectual developmental disorder with autism spectrum features, predominantly through loss-of-function mechanisms. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the primary disease mechanism.

OMIMResearchSummary from RefSeq, OMIM, Mechanism
LOFmechanismADLOEUF 0.051 OMIM phenotype
Clinical Summary— SYNGAP1
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

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 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
47 unique Pathogenic / Likely Pathogenic· 36 VUS of 100 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.05LOEUF
pLI 1.000
Z-score 6.97
OE 0.00 (0.00–0.05)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
5.60Z-score
OE missense 0.44 (0.40–0.48)
351 obs / 796.0 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.05)
0≤0.351.4
Missense OE0.44 (0.40–0.48)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 0 / 56.5Missense obs/exp: 351 / 796.0Syn Z: 1.65
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSYNGAP1-related intellectual developmental disorderLOFAD
DN
0.2997th %ile
GOF
0.3887th %ile
LOF
0.87top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 74% of P/LP variants are LoF · LOEUF 0.05

Literature Evidence

LOFHaploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice.PMID:27827368

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

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic22
VUS36
Likely Benign5
Benign2
Conflicting10
25
Pathogenic
22
Likely Pathogenic
36
VUS
5
Likely Benign
2
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
24
1
0
0
25
Likely Pathogenic
11
8
3
0
22
VUS
0
35
1
0
36
Likely Benign
0
2
0
3
5
Benign
0
2
0
0
2
Conflicting
—10
Total354843100

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

View in ClinVar →

Protein Context — Lollipop Plot

SYNGAP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients