SYNGAP1

Chr 6AD

synaptic Ras GTPase activating protein 1

Also known as: MRD5, RASA5, SYNGAP

NCBI Gene: 8831 ENSG00000197283 UniProt: Q96PV0 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 5MIM #612621

Clinical highlights

Management implications

SYNGAP1 has therapies in development

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2019
Definitive · intellectual disability, autosomal dominant 5 · AD · G2P
Supportive · myoclonic-astatic epilepsy · Unknown · Orphanet
Supportive · SYNGAP1-related developmental and epileptic encephalopathy · AD · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.05

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — SYNGAP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

SYNGAP1-upregulation programs
ASOPreclinical
Increase SYNGAP1 to counter haploinsufficiency.
Delivery: Intrathecal

Therapeutic landscape as of 2026-07. Educational only. Investigational ≠ available; not medical advice or eligibility. Approved entries are precise; investigational program names/phases are conservative and move fast. Curated from FDA/EMA approvals and the clinical-trial literature; verify against current labeling + ClinicalTrials.gov.

ClinicalTrials.gov

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 OE?0.00 (0.00–0.05)

0≤0.351.4

Missense OE?0.44 (0.40–0.48)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 0 / 56.5Missense obs/exp: 351 / 796.0Syn Z: 1.65

Background carrier burden — how many people carry a rare variant somewhere in SYNGAP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 85

1,051 rare PASS variants

Rare truncating (LoF)

1 in 230

104 rare PASS variants

Rare synonymous (reference)

1 in 68

645 rare PASS variants

Rare missense and truncating variants are carried at similar rates in SYNGAP1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 350
South Asian	~43k	1 in 82	1 in 430
Remaining (unassigned)	~30k	1 in 130	1 in 330
European (Finnish)	~27k	1 in 150	1 in 270
Admixed American	~22k	1 in 110	1 in 220
African / African American	~21k	1 in 110	1 in 240
East Asian	~20k	1 in 110	1 in 190
Ashkenazi Jewish	~13k	1 in 270	1 in 290
Middle Eastern	~2,884	1 in 120	1 in 260

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 19 coding exons well covered in gnomAD exomes; exon 14 poorly covered; exon 1 marginal. Genomes: 17 of 19 (exons 1, 19 below).? see exons ↓