SYNGAP1

Summary

SYNGAP1 (synaptic Ras GTPase activating protein 1, HGNC:11497) is a protein-coding gene on chromosome 6p21.32, encoding Ras/Rap GTPase-activating protein SynGAP (Q96PV0). Major constituent of the PSD essential for postsynaptic signaling. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 8831 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,798 total — 287 pathogenic, 102 likely-pathogenic
• Phenotypes (HPO): 121
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006772

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11497
Approved symbol	SYNGAP1
Name	synaptic Ras GTPase activating protein 1
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	SYNGAP, RASA5, KIAA1938
Ensembl gene	ENSG00000197283
Ensembl biotype	protein_coding
OMIM	603384
Entrez	8831

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 17 protein_coding_CDS_not_defined, 9 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000293748, ENST00000418600, ENST00000428982, ENST00000449372, ENST00000470232, ENST00000479510, ENST00000628646, ENST00000629380, ENST00000635885, ENST00000636075, ENST00000636116, ENST00000636146, ENST00000636193, ENST00000636436, ENST00000636443, ENST00000636640, ENST00000636731, ENST00000637052, ENST00000637194, ENST00000637490, ENST00000637587, ENST00000637671, ENST00000637721, ENST00000637911, ENST00000638127, ENST00000638142, ENST00000644458, ENST00000645250, ENST00000646630, ENST00000682587

RefSeq mRNA: 2 — MANE Select: NM_006772 NM_001130066, NM_006772

CCDS: CCDS34434, CCDS93894

Canonical transcript exons

ENST00000455687 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 98.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7637 / max 293.8503, expressed in 1690 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67293	3.4949	786
67297	3.3814	1267
67302	2.6799	499
67296	2.0962	978
67295	1.2109	422
67300	0.5558	206
67304	0.4152	148
67299	0.3520	169
67301	0.3513	154
67290	0.3433	90

Top tissues by expression

137 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	98.52	gold quality
right uterine tube	UBERON:0001302	98.41	gold quality
adenohypophysis	UBERON:0002196	98.08	gold quality
right ovary	UBERON:0002118	97.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.85	gold quality
body of uterus	UBERON:0009853	96.68	gold quality
left ovary	UBERON:0002119	96.66	gold quality
superior frontal gyrus	UBERON:0002661	96.55	gold quality
endocervix	UBERON:0000458	96.24	gold quality
cerebellar hemisphere	UBERON:0002245	96.07	gold quality
cerebellar cortex	UBERON:0002129	96.02	gold quality
myometrium	UBERON:0001296	95.98	gold quality
cerebellum	UBERON:0002037	95.97	gold quality
ovary	UBERON:0000992	95.77	gold quality
left uterine tube	UBERON:0001303	95.77	gold quality
right frontal lobe	UBERON:0002810	95.72	gold quality
endometrium	UBERON:0001295	95.38	gold quality
cortical plate	UBERON:0005343	95.11	gold quality
ectocervix	UBERON:0012249	94.69	gold quality
nucleus accumbens	UBERON:0001882	94.66	gold quality
right coronary artery	UBERON:0001625	94.62	gold quality
vagina	UBERON:0000996	94.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.50	gold quality
mucosa of stomach	UBERON:0001199	94.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.29	gold quality
lower esophagus	UBERON:0013473	94.28	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.24	gold quality
Ammon’s horn	UBERON:0001954	94.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.96	gold quality
anterior cingulate cortex	UBERON:0009835	93.96	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2A

miRNA regulators (miRDB)

178 targeting SYNGAP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4525	99.94	64.38	675

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 36)

• The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction. (PMID:18323856)
• Results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation. (PMID:19196676)
• These data suggest that NMDA receptor complex formation, localization, and downstream signaling may be abnormal in schizophrenia as PSD95, SynGAP and MUPP1 expression is altered. (PMID:19483657)
• We provide evidence that truncating mutations in SYNGAP1 are common in nonsyndromic intellectual disability and can be also associated with autism. (PMID:21237447)
• SYNGAP1 is a brain-specific protein that interacts with key components of the proteins involved in experience-dependent changes in glutamate synapses involved in learning. (PMID:21480541)
• De novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function, causing intellectual disability, autism, and a specific form of epilepsy. (PMID:23161826)
• De novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. (PMID:23708187)
• Reduced cognition in mutant Syngap1 transgenic mice is caused by isolated damage to developing forebrain neurons. (PMID:24945774)
• Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases. (PMID:25533468)
• De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. (PMID:26079862)
• This is the first description of a special electroencephalogram phenomenon (normalization with eye opening) in association with SYNGAP1 mutations. (PMID:26110312)
• Syngap transgenic mice exhibited alterations in long-term depression and dendritic spine morphology. (PMID:26558778)
• our findings suggest that SYNGAP1 variants are causative for ID, which expands our knowledge of the disease spectrum and provides new information on the genotype-phenotype relationship. (PMID:29381230)
• Complement receptor 3 (Integrin alpha-M beta-2)-mediated phagocytosis of Francisella due to increased ras GTPase-activating protein (RasGAP) activity. (PMID:29632532)
• The SYNGAP1 mutations cause a generalized developmental and epileptic encephalopathy with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures. (PMID:30541864)
• This study demonstrated that eating induced seizures in association with SYNGAP1 mutations. (PMID:30685520)
• SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. (PMID:31025938)
• A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. (PMID:31395010)
• Discussion on the clinical spectrum and molecular pathophysiology of SYNGAP1 mutations, aiming to understand how mutations in this protein affect neuronal development and function and how that translates into the clinical features observed in Mental retardation-type 5 patients (review). (PMID:31454529)
• SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons. (PMID:32887745)
• Distinct patterns of repetition suppression in Fragile X syndrome, down syndrome, tuberous sclerosis complex and mutations in SYNGAP1. (PMID:33189692)
• Multi-parametric analysis of 57 SYNGAP1 variants reveal impacts on GTPase signaling, localization, and protein stability. (PMID:33308442)
• SYNGAP1-DEE: A visual sensitive epilepsy. (PMID:33639450)
• Differential auditory brain response abnormalities in two intellectual disability conditions: SYNGAP1 mutations and Down syndrome. (PMID:34130248)
• Rho-Rho-Kinase Regulates Ras-ERK Signaling Through SynGAP1 for Dendritic Spine Morphology. (PMID:35624196)
• Generation of an induced pluripotent stem cell line (SDQLCHi044-A) from a patient with autosomal dominant mental retardation type 5 harboring heterozygous mutation in SYNGAP1 gene. (PMID:36183676)
• The SYNGAP1 3’UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK. (PMID:36261283)
• Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing. (PMID:36917980)
• Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis. (PMID:37946050)
• Discovery of a non-canonical function of SYNGAP1 at early stages of human cortical neurogenesis. (PMID:37996527)
• Severe behavior problems in SYNGAP1-related disorder: A summary of 11 consecutive patients in a tertiary care specialty clinic. (PMID:38096660)
• [Correlation of early neurodevelopmental features of children with SYNGAP1 variants and their genotypes]. (PMID:38171555)
• SYNGAP1-related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights. (PMID:38563110)
• The Behavioral Profile of SYNGAP1-Related Intellectual Disability. (PMID:38657965)
• Visual social attention in SYNGAP1-related intellectual disability. (PMID:38698724)
• Behavioural and neurodevelopmental characteristics of SYNGAP1. (PMID:39148034)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	syngap1a	ENSDARG00000063713
danio_rerio	syngap1b	ENSDARG00000069765
mus_musculus	Syngap1	ENSMUSG00000067629
rattus_norvegicus	Syngap1	ENSRNOG00000000483
drosophila_melanogaster	RasGAP1	FBGN0004390
drosophila_melanogaster	raskol	FBGN0261570
caenorhabditis_elegans		WBGENE00001515
caenorhabditis_elegans		WBGENE00001516

Paralogs (10): RASAL2 (ENSG00000075391), RASAL3 (ENSG00000105122), RASA4 (ENSG00000105808), RASAL1 (ENSG00000111344), DAB2IP (ENSG00000136848), RASA1 (ENSG00000145715), RASA2 (ENSG00000155903), RASA4B (ENSG00000170667), RASA3 (ENSG00000185989), NF1 (ENSG00000196712)

Protein

Protein identifiers

Ras/Rap GTPase-activating protein SynGAP — Q96PV0 (reviewed: Q96PV0)

Alternative names: Neuronal RasGAP, Synaptic Ras GTPase-activating protein 1

All UniProt accessions (8): A0A0A0MQZ2, A0A1B0GW70, A0A1U9X8L0, A0A2R8Y6T2, A0A2R8YDS2, A0A804HJ92, B7ZCA0, Q96PV0

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Interacts with KLHL17, CAMK2A and CAMK2B. Interacts with MPDZ. Interacts with FAM81A; the interaction facilitates condensate formation via liquid-liquid phase separation.

Post-translational modifications. Phosphorylated by CaM-kinase II. Dephosphorylated upon NMDA receptor activation or SYNGAP1/MPDZ complex disruption. Phosphorylation by PLK2 promotes its activity.

Disease relevance. Intellectual developmental disorder, autosomal dominant 5 (MRD5) [MIM:612621] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD5 patients show global developmental delay with delayed motor development, hypotonia, moderate-to-severe intellectual disability, and severe language impairment. Epilepsy and autism can be present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C2 domain is required for RapGAP activity.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96PV0-1	1	yes
Q96PV0-2	2
Q96PV0-3	3
Q96PV0-4	4

RefSeq proteins (2): NP_001123538, NP_006763* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001849	PH_domain	Domain
IPR001936	RasGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR021887	DAB2P_C	Domain
IPR023152	RasGAP_CS	Conserved_site
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037779	SynGAP_PH	Domain
IPR039360	Ras_GTPase	Family
IPR057606	SynGAP1-like_PH	Domain

Pfam: PF00168, PF00616, PF12004, PF25321

UniProt features (65 total): modified residue 27, sequence variant 14, compositionally biased region 8, region of interest 7, domain 3, splice variant 3, chain 1, short sequence motif 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PV0-F1	60.43	0.23

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 485 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (27): 34, 39, 117, 371, 379, 385, 449, 466, 752, 766, 780, 823, 825, 828, 836, 840, 842, 876, 892, 895 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-162582	Signal Transduction
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling

MSigDB gene sets: 396 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_ASSOCIATIVE_LEARNING, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_CELL_CELL_SIGNALING

GO Biological Process (18): Ras protein signal transduction (GO:0007265), pattern specification process (GO:0007389), axonogenesis (GO:0007409), visual learning (GO:0008542), dendrite development (GO:0016358), receptor clustering (GO:0043113), regulation of MAPK cascade (GO:0043408), negative regulation of neuron apoptotic process (GO:0043524), negative regulation of Ras protein signal transduction (GO:0046580), regulation of synaptic plasticity (GO:0048167), regulation of long-term neuronal synaptic plasticity (GO:0048169), negative regulation of axonogenesis (GO:0050771), regulation of synapse structure or activity (GO:0050803), neuron apoptotic process (GO:0051402), maintenance of postsynaptic specialization structure (GO:0098880), regulation of intracellular signal transduction (GO:1902531), regulation of GTPase activity (GO:0043087), modulation of chemical synaptic transmission (GO:0050804)

GO Molecular Function (3): GTPase activator activity (GO:0005096), SH3 domain binding (GO:0017124), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), dendritic shaft (GO:0043198), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RAF/MAP kinase cascade	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of biological quality	2
GTPase activity	2
small GTPase-mediated signal transduction	1
multicellular organism development	1
multicellular organismal process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
visual behavior	1
associative learning	1
neuron projection development	1
anatomical structure development	1
plasma membrane	1
protein localization to membrane	1
MAPK cascade	1
regulation of intracellular signal transduction	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
modulation of chemical synaptic transmission	1
regulation of neuronal synaptic plasticity	1
axonogenesis	1
negative regulation of neuron projection development	1
negative regulation of neurogenesis	1
regulation of axonogenesis	1
apoptotic process	1
postsynaptic density organization	1
maintenance of synapse structure	1
regulation of signal transduction	1
intracellular signal transduction	1
regulation of hydrolase activity	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
enzyme activator activity	1
GTPase regulator activity	1
protein domain specific binding	1

Protein interactions and networks

STRING

1874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYNGAP1	DLG4	P78352	995
SYNGAP1	DLG3	Q92796	917
SYNGAP1	GRIN2B	Q13224	910
SYNGAP1	SHANK3	Q9BYB0	884
SYNGAP1	DLG2	Q15700	869
SYNGAP1	ULK2	Q8IYT8	847
SYNGAP1	DLGAP2	Q9P1A6	818
SYNGAP1	SHANK2	Q9UPX8	804
SYNGAP1	ULK1	O75385	753
SYNGAP1	DLGAP1	P78335	750
SYNGAP1	SHANK1	Q9Y566	747
SYNGAP1	PTCHD1	Q96NR3	726
SYNGAP1	GRIA1	P42261	726
SYNGAP1	NLGN3	Q9NZ94	705
SYNGAP1	CACNG2	Q9Y698	703

IntAct

92 interactions, top by confidence:

A	B	Type	Score
SYNGAP1	LDB1	psi-mi:“MI:0915”(physical association)	0.680
SYNGAP1	ELAVL3	psi-mi:“MI:0915”(physical association)	0.680
LDB1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.680
ELAVL3	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.680
SYNGAP1	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.620
SYNGAP1	ISL1	psi-mi:“MI:0915”(physical association)	0.620
SYNGAP1	H1-4	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	MID2	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
SUOX	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
NCK2	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
NTAQ1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
VENTX	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
TLX3	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	SPAG8	psi-mi:“MI:0915”(physical association)	0.560
EFHC1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
MKRN3	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
GUCD1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
TSSK3	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	DLG4	psi-mi:“MI:0915”(physical association)	0.550
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	YWHAE	psi-mi:“MI:0914”(association)	0.530
HCN1	SYNGAP1	psi-mi:“MI:0915”(physical association)	0.500
SYNGAP1	FXR1	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (209): SYNGAP1 (Affinity Capture-Western), SYNGAP1 (Affinity Capture-Western), SYNGAP1 (Affinity Capture-MS), SYNGAP1 (Two-hybrid), SYNGAP1 (Reconstituted Complex), SYNGAP1 (Reconstituted Complex), SYNGAP1 (Affinity Capture-Western), SYNGAP1 (Reconstituted Complex), SYNGAP1 (Affinity Capture-Western), SYNGAP1 (Two-hybrid), SYNGAP1 (Two-hybrid), SYNGAP1 (Two-hybrid), SYNGAP1 (Two-hybrid), SYNGAP1 (Two-hybrid), SYNGAP1 (Two-hybrid)

ESM2 similar proteins: A0A8M9QN10, A0JNT9, A9C3W3, E7FDW2, F6SEU4, O15085, O35711, O43147, O55156, O75334, O75335, P0CF95, P11929, P25054, P68907, P70302, P70478, P83093, P84903, P97433, P97434, Q0V9T6, Q13586, Q3UHC7, Q58CP9, Q5FWS6, Q5SXA9, Q5U464, Q5VWQ8, Q63312, Q674X7, Q69ZS8, Q6NXJ0, Q6P402, Q6P730, Q6WCQ1, Q80U12, Q86W92, Q8BSS9, Q8C8U0

Diamond homologs: A6QQ91, F6SEU4, P48423, P97526, Q14644, Q15283, Q28013, Q3UHC7, Q54Y08, Q5VWQ8, Q60790, Q6P730, Q86YV0, Q8C2K5, Q8MLZ5, Q8T498, Q96PV0, Q9QUH6, Q9QYJ2, Q9UJF2, Q9Z268, P58069, Q63713, O95294, P09851, P18963, P20936, P50904, P19158, P21359, P41823, P42680, Q04690, Q5M7N9, Q5T7P8, Q62746, Q99N80, P35608, C9J798, O43374

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
SYNGAP1	“up-regulates activity”	DLG4	binding
CDK5	“up-regulates activity”	SYNGAP1	phosphorylation
CAMK2A	“up-regulates activity”	SYNGAP1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cell Cycle Checkpoints	5	13.8×	8e-04
RHO GTPase Effectors	5	10.6×	2e-03
Membrane Trafficking	6	7.0×	2e-03
Vesicle-mediated transport	6	6.5×	3e-03
Signaling by Rho GTPases	6	6.4×	3e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	6	6.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
mRNA transport	5	25.3×	5e-04
neuron migration	5	12.9×	2e-03
nervous system development	8	7.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1798 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	287
Likely pathogenic	102
Uncertain significance	553
Likely benign	556
Benign	116

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012768	NM_006772.3(SYNGAP1):c.1303_1304dup (p.Leu435fs)	Pathogenic
1030154	NM_006772.3(SYNGAP1):c.654_655del (p.Phe218fs)	Pathogenic
1064788	NM_006772.3(SYNGAP1):c.936dup (p.Glu313fs)	Pathogenic
1070521	NM_006772.3(SYNGAP1):c.91C>T (p.Arg31Ter)	Pathogenic
1071251	NM_006772.3(SYNGAP1):c.2234del (p.Pro745fs)	Pathogenic
1071936	NM_006772.3(SYNGAP1):c.2387dup (p.Pro797fs)	Pathogenic
1072360	NM_006772.3(SYNGAP1):c.1534G>T (p.Glu512Ter)	Pathogenic
1073426	NM_006772.3(SYNGAP1):c.2717del (p.Leu906fs)	Pathogenic
1075175	NM_006772.3(SYNGAP1):c.190-2A>C	Pathogenic
1075709	NM_006772.3(SYNGAP1):c.1022_1023del (p.Gly341fs)	Pathogenic
1076713	NM_006772.3(SYNGAP1):c.1136C>A (p.Ser379Ter)	Pathogenic
1172596	NM_006772.3(SYNGAP1):c.3233_3255del (p.Val1078fs)	Pathogenic
1172636	NM_006772.3(SYNGAP1):c.3834dup (p.Ala1279fs)	Pathogenic
1184124	NM_006772.3(SYNGAP1):c.646C>T (p.Gln216Ter)	Pathogenic
1184918	NM_006772.3(SYNGAP1):c.3138del (p.Ser1047fs)	Pathogenic
1187644	NM_006772.3(SYNGAP1):c.1284T>A (p.Tyr428Ter)	Pathogenic
1200643	NM_006772.3(SYNGAP1):c.1602_1603del (p.Ser535fs)	Pathogenic
1216291	NM_006772.3(SYNGAP1):c.2197C>T (p.Gln733Ter)	Pathogenic
1285474	NM_006772.3(SYNGAP1):c.3269dup (p.Asn1090fs)	Pathogenic
130525	NM_006772.3(SYNGAP1):c.1783del (p.Leu595fs)	Pathogenic
130528	NM_006772.3(SYNGAP1):c.2602del (p.Asp868fs)	Pathogenic
1323672	NM_006772.3(SYNGAP1):c.2538dup (p.Gln847fs)	Pathogenic
1344972	NM_006772.3(SYNGAP1):c.1913+2T>G	Pathogenic
1386516	NM_006772.3(SYNGAP1):c.3369_3380del (p.Gly1125_Gly1128del)	Pathogenic
1393302	NM_006772.3(SYNGAP1):c.3516dup (p.Ile1173fs)	Pathogenic
1401359	NM_006772.3(SYNGAP1):c.3685C>T (p.Gln1229Ter)	Pathogenic
1401645	NM_006772.3(SYNGAP1):c.3303del (p.Ala1102fs)	Pathogenic
1404191	NM_006772.3(SYNGAP1):c.1640G>A (p.Cys547Tyr)	Pathogenic
1425584	NM_006772.3(SYNGAP1):c.2516dup (p.Ser840fs)	Pathogenic
1432487	NM_006772.3(SYNGAP1):c.1712C>A (p.Ser571Ter)	Pathogenic

SpliceAI

3339 predictions. Top by Δscore:

Variant	Effect	Δscore
6:33420329:GAG:G	donor_gain	1.0000
6:33423467:T:TA	acceptor_gain	1.0000
6:33423471:CTCCA:C	acceptor_loss	1.0000
6:33423472:TCCAG:T	acceptor_loss	1.0000
6:33423473:CCAG:C	acceptor_loss	1.0000
6:33423474:CAGA:C	acceptor_loss	1.0000
6:33423475:A:AG	acceptor_gain	1.0000
6:33423475:AGAT:A	acceptor_gain	1.0000
6:33423476:G:GT	acceptor_gain	1.0000
6:33423476:GAT:G	acceptor_gain	1.0000
6:33423476:GATG:G	acceptor_gain	1.0000
6:33423596:GAG:G	donor_gain	1.0000
6:33423597:AGG:A	donor_loss	1.0000
6:33423598:GGT:G	donor_loss	1.0000
6:33423599:G:GG	donor_gain	1.0000
6:33432684:GCAA:G	acceptor_gain	1.0000
6:33432788:G:GT	donor_gain	1.0000
6:33435511:CTA:C	acceptor_loss	1.0000
6:33435513:A:AT	acceptor_loss	1.0000
6:33435514:G:A	acceptor_loss	1.0000
6:33437641:A:AG	acceptor_gain	1.0000
6:33437642:A:G	acceptor_gain	1.0000
6:33437643:C:G	acceptor_gain	1.0000
6:33437644:A:AG	acceptor_gain	1.0000
6:33437644:ATCAT:A	acceptor_gain	1.0000
6:33437645:T:G	acceptor_gain	1.0000
6:33437648:T:G	acceptor_gain	1.0000
6:33437648:T:TA	acceptor_gain	1.0000
6:33437658:A:AG	acceptor_gain	1.0000
6:33437913:G:GT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000034328 (6:33428790 C>T), RS1000081481 (6:33443009 A>C,G), RS1000091919 (6:33420974 G>T), RS1000162416 (6:33431022 G>A), RS1000365033 (6:33447514 A>G,T), RS1000505124 (6:33447273 T>G), RS1000549464 (6:33422152 T>G), RS1000649767 (6:33426657 T>C), RS1000688704 (6:33442287 G>A), RS1000756206 (6:33439380 A>G), RS1001002952 (6:33427688 C>A,T), RS1001021641 (6:33427282 G>A), RS1001093191 (6:33419095 G>C), RS1001119007 (6:33442725 C>A), RS1001155842 (6:33424039 G>A)

Disease associations

OMIM: gene MIM:603384 | disease phenotypes: MIM:612621, MIM:611091

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 5	Definitive	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
myoclonic-astatic epilepsy	Supportive	Unknown
SYNGAP1-related developmental and epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (14): intellectual disability, autosomal dominant 5 (MONDO:0012960), hereditary ataxia (MONDO:0100309), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038), stereotypic movement disorder (MONDO:0002265), cerebellar ataxia (MONDO:0000437), ptosis (MONDO:0000728), infantile epilepsy syndrome (MONDO:0020071), intellectual disability, autosomal recessive 5 (MONDO:0012613), microcephaly (MONDO:0001149), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), (MONDO:0016025), (MONDO:0034099)

Orphanet (7): SYNGAP1-related developmental and epileptic encephalopathy (Orphanet:544254), Hereditary ataxia (Orphanet:183518), Non-specific syndromic intellectual disability (Orphanet:528084), Rare ataxia (Orphanet:102002), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: Infantile epilepsy syndrome (Orphanet:98258)

HPO phenotypes

121 total (30 of 121 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000289	Broad philtrum
HP:0000325	Triangular face
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000568	Microphthalmia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003815_17	Late-onset Alzheimer’s disease	8.000000e-06
GCST004521_251	Autism spectrum disorder or schizophrenia	6.000000e-12
GCST004521_287	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST004521_75	Autism spectrum disorder or schizophrenia	8.000000e-10
GCST005951_153	Body mass index	5.000000e-09
GCST007201_281	Schizophrenia	7.000000e-12
GCST007656_5	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	3.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease
EFO:0004340	body mass index

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D001763	Blepharoptosis	C11.338.204
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D019956	Stereotypic Movement Disorder	F03.625.984
C531684	Hereditary spinal ataxia (supp.)
C567234	Mental Retardation, Autosomal Dominant 5 (supp.)
C567018	Mental Retardation, Autosomal Recessive 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
beta-lapachone	increases expression	1
tebuconazole	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Glyphosate	decreases expression, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases abundance, decreases expression	1

Cellosaurus cell lines

8 cell lines: 3 induced pluripotent stem cell, 3 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5MK	GM27901	Transformed cell line	Female
CVCL_A5ML	GM27957	Induced pluripotent stem cell	Female
CVCL_C1WD	SDQLCHi044-A	Induced pluripotent stem cell	Male
CVCL_C8DX	SDQLCHi053-A	Induced pluripotent stem cell	Female
CVCL_D6XW	GM28873	Transformed cell line	Female
CVCL_E2LD	HAP1 SYNGAP1 (-) 1	Cancer cell line	Male
CVCL_E2LE	HAP1 SYNGAP1 (-) 2	Cancer cell line	Male
CVCL_E2LF	HAP1 SYNGAP1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01360164	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Therapy for Patients With Hereditary Ataxia
NCT00004306	Not specified	COMPLETED	Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 10 (SCA10)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04750850	Not specified	COMPLETED	Core Stability Exercises and Hereditary Ataxia
NCT05160870	Not specified	UNKNOWN	Genotype-phenotype Correlation and Pathogenic Mechanism in Hereditary Ataxia
NCT05160883	Not specified	UNKNOWN	Neuroimaging Changes in Hereditary Ataxia
NCT06034886	Not specified	AVAILABLE	Expanded Access Protocol of Troriluzole in Patients With Spinocerebellar Ataxia (SCA)
NCT06152133	Not specified	COMPLETED	Telerehabilitation, Core Stability Exercises and Hereditary Ataxia (TRCore-ataxia)
NCT06267222	Not specified	ENROLLING_BY_INVITATION	Trans-spinal Electrical Stimulation in Individuals With Spinocerebellar Ataxia
NCT07092358	Not specified	RECRUITING	Hereditary Ataxia Research on Multi-Omics and Neuroclinical Insights in the Yangtze Delta
NCT07200505	Not specified	NOT_YET_RECRUITING	Telerehabilitation for Core Stability and Strength in Hereditary Ataxia
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior