SRGAP2

Summary

SRGAP2 (SLIT-ROBO Rho GTPase activating protein 2, HGNC:19751) is a protein-coding gene on chromosome 1q32.1, encoding SLIT-ROBO Rho GTPase-activating protein 2 (O75044). Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex.

This locus encodes a member of the SLIT-ROBO Rho GTPase activating protein family. The encoded protein stimulates GTPase activity of Rac1, and plays a role in cortical neuron development. This locus has several paralogs on human chromosome 1 resulting from segmental duplication. While this locus itself is conserved among various species, the paralogs are found only in the genus Homo, and not in the genomes of non-human great apes. Alternatively spliced transcript variants have been described for this locus.

Source: NCBI Gene 23380 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 6 total — 2 likely-pathogenic
• MANE Select transcript: NM_015326

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19751
Approved symbol	SRGAP2
Name	SLIT-ROBO Rho GTPase activating protein 2
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0456, ARHGAP34, SRGAP2A
Ensembl gene	ENSG00000266028
Ensembl biotype	protein_coding
OMIM	606524
Entrez	23380

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 TEC

ENST00000419187, ENST00000572793, ENST00000573034, ENST00000603575, ENST00000603708, ENST00000604010, ENST00000604133, ENST00000604247, ENST00000604419, ENST00000604423, ENST00000604925, ENST00000605242, ENST00000605476, ENST00000605610, ENST00000624686, ENST00000624873, ENST00000934486, ENST00000934487

RefSeq mRNA: 7 — MANE Select: NM_015326 NM_001170637, NM_001300952, NM_001377444, NM_001377445, NM_001377446, NM_001377447, NM_015326

CCDS: CCDS73017, CCDS76261, CCDS76262

Canonical transcript exons

ENST00000573034 — 23 exons

Exon	Start	End
ENSE00002704962	206203541	206203650
ENSE00002725670	206205429	206206037
ENSE00003473473	206446075	206446299
ENSE00003477765	206454878	206455024
ENSE00003506333	206458623	206458947
ENSE00003521660	206461037	206464436
ENSE00003534898	206419373	206419400
ENSE00003558763	206439976	206440081
ENSE00003570284	206430162	206430222
ENSE00003572197	206421250	206421274
ENSE00003608374	206453200	206453380
ENSE00003613019	206406377	206406574
ENSE00003628732	206437964	206438098
ENSE00003636573	206401421	206401645
ENSE00003637885	206384014	206384076
ENSE00003649875	206450386	206450465
ENSE00003658603	206415889	206415973
ENSE00003668782	206342846	206343008
ENSE00003672379	206436965	206437042
ENSE00003730945	206392689	206392904
ENSE00003733425	206405249	206405350
ENSE00003745335	206393545	206393673
ENSE00003784641	206303281	206303473

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.63.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0093 / max 6.4053, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8082	0.0093	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	98.63	gold quality
cerebellar cortex	UBERON:0002129	98.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.43	gold quality
cerebellum	UBERON:0002037	98.06	gold quality
sural nerve	UBERON:0015488	98.04	gold quality
cortical plate	UBERON:0005343	97.99	gold quality
paraflocculus	UBERON:0005351	97.04	gold quality
ventricular zone	UBERON:0003053	96.24	gold quality
skin of leg	UBERON:0001511	95.66	gold quality
ganglionic eminence	UBERON:0004023	95.33	gold quality
tibial nerve	UBERON:0001323	95.27	gold quality
skin of abdomen	UBERON:0001416	95.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.47	gold quality
adrenal tissue	UBERON:0018303	94.46	gold quality
monocyte	CL:0000576	93.15	gold quality
spinal cord	UBERON:0002240	93.07	gold quality
corpus callosum	UBERON:0002336	93.01	gold quality
mononuclear cell	CL:0000842	92.75	gold quality
right lung	UBERON:0002167	92.66	gold quality
leukocyte	CL:0000738	92.55	gold quality
zone of skin	UBERON:0000014	92.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.28	gold quality
omental fat pad	UBERON:0010414	91.99	gold quality
peritoneum	UBERON:0002358	91.96	gold quality
upper lobe of left lung	UBERON:0008952	90.97	gold quality
calcaneal tendon	UBERON:0003701	90.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.70	gold quality
right adrenal gland	UBERON:0001233	90.61	gold quality
prefrontal cortex	UBERON:0000451	90.59	gold quality
right frontal lobe	UBERON:0002810	90.53	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	3788.32
E-HCAD-25	yes	2526.25
E-HCAD-35	yes	48.26
E-CURD-119	yes	33.37
E-ANND-3	yes	10.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN

miRNA regulators (miRDB)

145 targeting SRGAP2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695

Literature-anchored findings (GeneRIF, showing 16)

• FNBP2 gene was linked to IKBKE and NORE1 genes on human chromosome 1q32.1. FNBP2 mRNA was expressed in melanoma, germ cell tumors, chondrosarcoma and retinoblastoma. (PMID:12736724)
• srGAP2 arginine methylation plays important roles in cell spreading and cell migration through influencing membrane protrusion. (PMID:20810653)
• after Rac-dependent activation of FMNL1, srGAP2 mediates a potent mechanism to limit the duration of Rac action and inhibit formin activity during rapid actin dynamics. (PMID:21148482)
• SRGAP2 has been highly conserved over mammalian evolution, and human is the only lineage wherein gene duplications have occurred. Our analysis indicates that the duplications spread across 80 Mbp of chromosome 1 at a time corresponding to the transition from Australopithecus to Homo. (PMID:22559943)
• Results uncover a new function for ancestral SRGAP2 in promoting dendritic spine maturation and indicate that expression of a human-specific paralog of SRGAP2 in mouse pyramidal neurons extends the phase of spine development and leads to an increased density of longer spines in vivo, a feature characterizing pyramidal neurons in the human neocortex (PMID:22559944)
• This study illustrated that the role of SRGAP2 protein and its human-specific paralogs in human brain development and evolution. (PMID:23782070)
• interlocus gene conversions in SRGAP2 (PMID:23892896)
• human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance (PMID:27373832)
• The extended F-BAR (F-BARx) domain of SRGAP2 generates membrane protrusions when expressed in COS-7 cells, while most F-BARs induce the opposite effect: membrane invaginations. As a first step to understand this discrepancy, the F-BARx domain of SRGAP2 was isolated and crystallized after co-expression with the carboxy domains of the protein. Diffraction data were reprocessed with a high-resolution cutoff of 2.2 A. (PMID:27917825)
• Results show that in high-grade, stage II osteosarcoma samples, expression of SRGAP2 was substantially reduced or absent in over half of the samples. Functional analysis provides further evidence that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. (PMID:27966608)
• These results indicated that the SRGAP2 SNPs and their haplotypes were associated with serum lipid levels. Their haplotypes can explain much more serum lipid variation than any single SNP alone, especially for serum TC, HDL-C and ApoA1 levels. (PMID:28912560)
• SRGAP2a protects podocytes in diabetic nephropathy by suppressing podocyte migration. (PMID:29242313)
• Identification of SRGAP2 as a potential oncogene and a prognostic biomarker in hepatocellular carcinoma. (PMID:33984363)
• SRGAP2 controls colorectal cancer chemosensitivity via regulation of mitochondrial complex I activity. (PMID:36059022)
• Tumor-Derived Exosomal miR-29b Reduces Angiogenesis in Pancreatic Cancer by Silencing ROBO1 and SRGAP2. (PMID:36277474)
• Stiff matrix induced srGAP2 tension gradients control migration direction in triple-negative breast cancer. (PMID:36593959)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	srgap2	ENSDARG00000032161
mus_musculus	Srgap2	ENSMUSG00000026425
rattus_norvegicus	Srgap2	ENSRNOG00000006733
caenorhabditis_elegans		WBGENE00006406

Paralogs (5): ARHGAP4 (ENSG00000089820), SRGAP2C (ENSG00000171943), SRGAP3 (ENSG00000196220), SRGAP2B (ENSG00000196369), SRGAP1 (ENSG00000196935)

Protein

Protein identifiers

SLIT-ROBO Rho GTPase-activating protein 2 — O75044 (reviewed: O75044)

Alternative names: Formin-binding protein 2, Rho GTPase-activating protein 34

All UniProt accessions (8): A0A075B743, O75044, A0A075B7B5, A0A075B7E6, A0A075B7E9, B7ZM87, E9PDX4, Q5VZB4

UniProt curated annotations — full annotation on UniProt →

Function. Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex. Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons. SRGAP2/SRGAP2A limits excitatory and inhibitory synapse density through its RAC1-specific GTPase activating activity, while it promotes maturation of both excitatory and inhibitory synapses through its ability to bind to the postsynaptic scaffolding protein HOMER1 at excitatory synapses, and the postsynaptic protein GPHN at inhibitory synapses. Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation. Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions. In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia.

Subunit / interactions. Homodimer. Heterodimer; forms a heterodimer with SRGAP2C, altering SRGAP2 function. Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain. Interacts (via SH3 domain) with GPHN. Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics. Interacts (via SH3 domain) with FMNL3. Interacts with RAC1; specifically stimulates RAC1 GTPase activity. Interacts (via F-BAR domain) with HOMER1. Interacts with ROBO1 and ROBO2. Interacts with FASLG. Interacts with PRMT5.

Subcellular location. Cell membrane. Cell projection. Dendritic spine. Postsynaptic density. Postsynaptic cell membrane. Lamellipodium. Cytoplasmic vesicle. Phagosome. Nucleus. Cytoplasm. Cytosol.

Post-translational modifications. Methylation at Arg-927 is required for the stimulation of cell migration, dimerization and localization at the plasma membrane protrusions.

Disease relevance. A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13).

Activity regulation. Activity is strongly inhibited by SRGAP2C, which heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation.

Domain organisation. The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.

Miscellaneous. There are 3 duplications of SRGAP2 in the human genome as a result of segmental gene duplications. SRGAP2C is the only one to be fixed at a diploid state in the human genome. Moreover, SRGAP2C is functional, interacts with and inhibits SRGAP2 and is human-specific. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years ago, which corresponds to the beginning of neocortex expansion in human evolution and it may have played an important role in this process through its interaction with SRGAP2 function.

RefSeq proteins (7): NP_001164108, NP_001287881, NP_001364373, NP_001364374, NP_001364375, NP_001364376, NP_056141* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR001060	FCH_dom	Domain
IPR001452	SH3_domain	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR031160	F_BAR_dom	Domain
IPR035648	srGAP1/2/3_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051627	SLIT-ROBO_RhoGAP	Family

Pfam: PF00018, PF00611, PF00620

UniProt features (68 total): helix 15, modified residue 14, mutagenesis site 10, compositionally biased region 7, strand 7, region of interest 5, domain 3, coiled-coil region 2, chain 1, site 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4RUG	X-RAY DIFFRACTION	1.73
4RTT	X-RAY DIFFRACTION	1.87
5I6R	X-RAY DIFFRACTION	2.15
5I6J	X-RAY DIFFRACTION	2.7
5I7D	X-RAY DIFFRACTION	3.95
2DL8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75044-F1	72.59	0.46

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): 527 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (14): 206, 427, 500, 691, 695, 724, 795, 916, 927, 930, 990, 994, 1013, 1027

Mutagenesis-validated functional residues (10):

Position	Phenotype
54–55	in f-barx-r5e mutant; abolished binding to membranes; when associated with 234–e–e-238.
108	does not affect protein stability.
108	decreased protein stability.
234–238	in f-barx-r5e mutant; abolished binding to membranes; when associated with 54-e-e-55.
527	abolished rac1 gtpase activity; when associated with a-566.
566	abolished rac1 gtpase activity; when associated with l-527.
765	abolished interaction with robo1.
781	abolished interaction with robo1.
807	increased interaction with robo1.
927	loss of the ability to stimulate cell migration, to localize at the plasma membrane protrusions and to dimerize.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-428543	Inactivation of CDC42 and RAC1
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-376176	Signaling by ROBO receptors
R-HSA-422475	Axon guidance
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 330 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_DENDRITE_DEVELOPMENT, TGGTGCT_MIR29A_MIR29B_MIR29C, GNF2_RTN1, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, BROWNE_HCMV_INFECTION_6HR_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_SYNAPSE_ASSEMBLY, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOMF_GTPASE_BINDING

GO Biological Process (17): lamellipodium assembly involved in ameboidal cell migration (GO:0003363), signal transduction (GO:0007165), nervous system development (GO:0007399), extension of a leading process involved in cell motility in cerebral cortex radial glia guided migration (GO:0021816), negative regulation of cell migration (GO:0030336), substrate adhesion-dependent cell spreading (GO:0034446), positive regulation of GTPase activity (GO:0043547), filopodium assembly (GO:0046847), neuron projection morphogenesis (GO:0048812), actin filament severing (GO:0051014), regulation of small GTPase mediated signal transduction (GO:0051056), regulation of synapse assembly (GO:0051963), dendritic spine development (GO:0060996), excitatory synapse assembly (GO:1904861), inhibitory synapse assembly (GO:1904862), negative regulation of neuron migration (GO:2001223), regulation of cell migration (GO:0030334)

GO Molecular Function (5): GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (15): nucleus (GO:0005634), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), lamellipodium (GO:0030027), dendritic spine (GO:0043197), dendritic spine head (GO:0044327), postsynaptic membrane (GO:0045211), phagocytic vesicle (GO:0045335), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RHO GTPase cycle	6
Signaling by Rho GTPases	2
Signaling by ROBO receptors	1
RHO GTPase Effectors	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
synapse assembly	3
cell migration	2
GTPase activity	2
cytoplasm	2
postsynapse	2
ameboidal-type cell migration	1
lamellipodium assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
modulation of microtubule cytoskeleton involved in cerebral cortex radial glia guided migration	1
pseudopodium assembly	1
regulation of cell migration	1
negative regulation of cell motility	1
cell-substrate adhesion	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
plasma membrane bounded cell projection assembly	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
actin filament-based process	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
regulation of synapse organization	1
regulation of cell junction assembly	1
dendrite development	1
anatomical structure development	1
neuron migration	1
negative regulation of cell migration	1
regulation of neuron migration	1
regulation of cell motility	1
enzyme activator activity	1
GTPase regulator activity	1
GTPase binding	1
protein binding	1
identical protein binding	1

Protein interactions and networks

STRING

1570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRGAP2	FMNL1	O95466	899
SRGAP2	HYDIN	Q4G0P3	877
SRGAP2	GPRIN2	O60269	858
SRGAP2	NBPF1	Q3BBV0	850
SRGAP2	UGT2B17	O75795	823
SRGAP2	NPEPPS	P55786	822
SRGAP2	ROBO1	Q9Y6N7	796
SRGAP2	GTF2I	P78347	796
SRGAP2	WASL	O00401	776
SRGAP2	DRD5	P21918	772
SRGAP2	TRIP10	Q15642	772
SRGAP2	SLIT3	O75094	734
SRGAP2	SLIT1	O75093	726
SRGAP2	ROBO2	Q9HCK4	640
SRGAP2	FAM131B	Q86XD5	625

IntAct

186 interactions, top by confidence:

A	B	Type	Score
SRGAP2	YWHAG	psi-mi:“MI:0915”(physical association)	0.870
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAZ	SRGAP2	psi-mi:“MI:0915”(physical association)	0.820
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
SRGAP2	SRGAP2	psi-mi:“MI:0407”(direct interaction)	0.740
SRGAP2	SRGAP2	psi-mi:“MI:0915”(physical association)	0.740
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
SRGAP2	FASLG	psi-mi:“MI:0407”(direct interaction)	0.610
SRGAP2	PRMT5	psi-mi:“MI:0915”(physical association)	0.610
PRMT5	SRGAP2	psi-mi:“MI:0915”(physical association)	0.610
PRMT5	SRGAP2	psi-mi:“MI:0407”(direct interaction)	0.610
SRGAP2	PRMT5	psi-mi:“MI:0213”(methylation reaction)	0.610
SRGAP2	FASLG	psi-mi:“MI:0915”(physical association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
SRGAP2	FMNL1	psi-mi:“MI:0915”(physical association)	0.600
FMNL1	SRGAP2	psi-mi:“MI:0915”(physical association)	0.600
SRGAP2	FMNL1	psi-mi:“MI:0407”(direct interaction)	0.600
SRGAP2	ROBO1	psi-mi:“MI:0407”(direct interaction)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
TRIML2	SRGAP2	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (194): SRGAP2 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS), SRGAP2 (Proximity Label-MS), SRGAP2 (Proximity Label-MS), SRGAP2 (Affinity Capture-MS), SRGAP2 (Proximity Label-MS), SRGAP2 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), LRFN1 (Affinity Capture-MS)

ESM2 similar proteins: A1XBS5, B0S6J3, D4A208, O35180, O35964, O43295, O75044, P0DJJ0, P0DMP2, P25343, Q08DK5, Q15057, Q1LU86, Q1RMK1, Q2VR06, Q32LM0, Q3SZG6, Q3V2J0, Q5AFE4, Q5FVC7, Q5PPJ9, Q5PPZ5, Q5R8P5, Q5ZIR1, Q5ZJ81, Q5ZK62, Q62419, Q62421, Q68FW8, Q6AYE2, Q6GN09, Q6IVG4, Q6ZQK5, Q6ZTR7, Q7Z6B7, Q812A2, Q8AXU9, Q8BP22, Q8I190, Q8I1C0

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, A7A261, B0S6J3, B1V8A0, D4A208, F1LM93, F1LXF1, F1RDG9, O35413, O43295, O75044, O94875, P00523, P00525, P05480, P06241, P07947, P09324, P09769, P0DJJ0, P0DMP2, P10936, P11274, P12931, P13115, P13116, P13406, P14084, P14085, P15054, P15882, P19706, P27446, P27447, P30337, P32793, P39688, P42686

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SRGAP2	“down-regulates activity”	RAC1	“gtpase-activating protein”
SRGAP2	“down-regulates activity”	CDC42	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	53.5×	1e-11
Activation of BAD and translocation to mitochondria	7	47.2×	8e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	41.6×	2e-08
Activation of BH3-only proteins	7	30.8×	2e-07
RHO GTPases activate PKNs	10	28.1×	4e-10
Intrinsic Pathway for Apoptosis	7	18.1×	5e-06
FOXO-mediated transcription	5	14.9×	5e-04
Apoptosis	9	13.4×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	14.0×	3e-03
substantia nigra development	5	11.7×	8e-03
ephrin receptor signaling pathway	5	10.9×	9e-03
cellular response to insulin stimulus	7	7.6×	7e-03
intracellular protein localization	9	6.0×	6e-03
negative regulation of cell migration	8	5.7×	9e-03
protein phosphorylation	11	4.8×	6e-03
cilium assembly	10	4.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
495282	NC_000001.10:g.(?206579711)(206634815_?)dup	Likely pathogenic
495283	NC_000001.10:g.(?206516175)(206567055_?)dup	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

7136 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:206303296:T:C	L28P	1.000
1:206303347:T:C	L45P	1.000
1:206303359:T:C	L49P	1.000
1:206303374:G:C	R54P	1.000
1:206303382:G:C	A57P	1.000
1:206303403:T:C	S64P	1.000
1:206303407:G:C	R65P	1.000
1:206303413:T:C	L67P	1.000
1:206303422:T:C	L70P	1.000
1:206303431:G:C	R73P	1.000
1:206342880:T:A	W99R	1.000
1:206342880:T:C	W99R	1.000
1:206342890:T:C	L102P	1.000
1:206342908:G:C	R108P	1.000
1:206342932:T:C	L116P	1.000
1:206384069:T:C	L160P	1.000
1:206392701:T:G	Y167D	1.000
1:206392731:G:C	A177P	1.000
1:206392740:A:G	K180E	1.000
1:206392744:T:C	L181P	1.000
1:206392752:G:C	A184P	1.000
1:206393545:C:A	R235S	1.000
1:206393546:G:C	R235P	1.000
1:206393554:A:G	K238E	1.000
1:206393556:G:C	K238N	1.000
1:206393556:G:T	K238N	1.000
1:206393587:G:C	A249P	1.000
1:206393591:G:C	R250P	1.000
1:206401452:T:C	L288P	1.000
1:206401464:T:C	L292P	1.000

dbSNP variants (sampled 300 via entrez): RS1000048591 (1:206451342 T>C), RS1000349256 (1:206431650 C>T), RS1000509883 (1:206447018 G>A,T), RS1000582038 (1:206445300 G>T), RS1000742423 (1:206433256 G>A), RS1000841295 (1:206427254 T>C), RS1000966363 (1:206446738 C>A), RS1001000964 (1:206420959 T>C), RS1001046130 (1:206464556 C>G,T), RS1001109613 (1:206464149 G>A,T), RS1001235727 (1:206452489 T>C), RS1001460024 (1:206421152 G>A,T), RS1001859952 (1:206440780 C>G,T), RS1001976767 (1:206432462 G>A), RS1002084219 (1:206434133 G>A)

Disease associations

OMIM: gene MIM:606524 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): intellectual disability (MONDO:0001071), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (2): Non-specific early-onset epileptic encephalopathy (Orphanet:442835), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001704_1	Cholesterol and Triglycerides	9.000000e-07
GCST009379_3	Type 2 diabetes	2.000000e-08
GCST010002_375	Refractive error	2.000000e-54
GCST010042_106	Asthma	1.000000e-09
GCST010043_91	Asthma	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	4
Acetaminophen	increases expression	3
Valproic Acid	affects cotreatment, increases expression	3
bisphenol A	decreases expression, increases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	decreases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric oxide	decreases expression	1
triacsin C	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Acrolein	decreases expression, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Cisplatin	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
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
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)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders