SYNGAP1

Chr 6AD

synaptic Ras GTPase activating protein 1

NCBI Gene: 8831ENSG00000197283UniProt: Q96PV0

Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR-mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term learning and memory deficits (By similarity)

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 5MIM #612621
AD
1920
ClinVar variants
129
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— SYNGAP1
⚡
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.
📋
ClinVar Variants
129 Pathogenic / Likely Pathogenic· 218 VUS of 1920 total submissions
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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.05LOEUF
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?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.
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?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.0.00 (0.00–0.05)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.40–0.48)
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.0.88
0≤1.21.6
LoF obs/exp: 0 / 56.5Missense obs/exp: 351 / 796.0Syn Z: 1.65

ClinVar Variant Classifications

1920 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic83
Likely Pathogenic46
VUS218
Likely Benign115
Benign11
Conflicting12
83
Pathogenic
46
Likely Pathogenic
218
VUS
115
Likely Benign
11
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
59
1
23
0
83
Likely Pathogenic
19
17
9
1
46
VUS
0
187
26
5
218
Likely Benign
0
11
39
65
115
Benign
0
10
1
0
11
Conflicting
—12
Total782269871485

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.

Gene2Phenotype Curations

SYNGAP1-related intellectual developmental disorder

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 5

MIM #612621

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autism spectrum disorder: neuropathology and animal models.
Varghese M et al.·Acta Neuropathol
2017Review
SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.
Vlaskamp DRM et al.·Neurology
2019
Clinical experience with non-invasive prenatal screening for single-gene disorders.
Mohan P et al.·Ultrasound Obstet Gynecol
2022
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing.
Bruno LP et al.·Int J Mol Sci
2021Clinical trial
SYNGAP1-Related Intellectual Disability: Meaningful Clinical Outcomes and Development of a Disease Concept Model Draft.
Cunnane KA et al.·Pediatr Neurol
2025Review
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
Carvill GL et al.·Nat Genet
2013
SYNGAP1 mutations: Clinical, genetic, and pathophysiological features.
Agarwal M et al.·Int J Dev Neurosci
2019Review
Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox-Gastaut Syndrome.
Lattanzi S et al.·CNS Drugs
2021Review
Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies.
Samanta D et al.·Pediatr Neurol
2025Review
Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment.
Dwivedi R et al.·Brain Res
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Research progress in SYNGAP1-related neurodevelopmental disorders: from pathogenesis to therapeutic strategies.
Zhang J et al.·Front Neurol
2026🔓 Open Access
Syngap1 and the development of murine neocortical progenitor cells.
Barão S et al.·Nat Commun
2025🔓 Open Access
Epigenetic regulation of SYNGAP1 in alcohol use disorder in whole blood and saliva.
Edelmann S et al.·Front Psychiatry
2025🔓 Open Access
De novo frameshift mutation in SYNGAP1 resulting in autosomal dominant mental retardation type 5 and autism spectrum disorder: a case report.
Lin S et al.·Front Pediatr
2025🔓 Open AccessCase report
Could the Polymorphisms of DOCK4 (rs147636134), SYNGAP1 (rs199759879), and FOXP1 (rs767001715) be the Primary Risk Factors for Bipolar Disorder and Autism Spectrum Disorder?
Çiftçi E et al.·Dev Neurobiol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
RAS MutationNeurofibromatosis 1Noonan Syndrome

RASopathy Biorepository

RECRUITING
NCT04395495Children's Hospital Medical Center, CincinnatiStarted 2017-06-27
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet
Genetic DiseaseSTXBP1 Encephalopathy With EpilepsySYNGAP1-Related Intellectual Disability

STXBP1 and SYNGAP1 Related Disorders Natural History Study

RECRUITING
NCT06555965Children's Hospital of PhiladelphiaStarted 2023-08-30
Non-interventional study

External Resources

Links to major genomics databases and tools