RAPGEF1

Summary

RAPGEF1 (Rap guanine nucleotide exchange factor 1, HGNC:4568) is a protein-coding gene on chromosome 9q34.13, encoding Rap guanine nucleotide exchange factor 1 (Q13905). Guanine nucleotide-releasing protein that binds to SH3 domain of CRK and GRB2/ASH.

This gene encodes a human guanine nucleotide exchange factor. It transduces signals from CRK by binding the SH3 domain of CRK, and activating several members of the Ras family of GTPases. This signaling cascade that may be involved in apoptosis, integrin-mediated signal transduction, and cell transformation. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined.

Source: NCBI Gene 2889 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 153 total
• MANE Select transcript: NM_001377935

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4568
Approved symbol	RAPGEF1
Name	Rap guanine nucleotide exchange factor 1
Location	9q34.13
Locus type	gene with protein product
Status	Approved
Aliases	C3G
Ensembl gene	ENSG00000107263
Ensembl biotype	protein_coding
OMIM	600303
Entrez	2889

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000372189, ENST00000372190, ENST00000372195, ENST00000414781, ENST00000419442, ENST00000438647, ENST00000481260, ENST00000683357, ENST00000914829, ENST00000914830, ENST00000914831, ENST00000914832, ENST00000914833, ENST00000914834, ENST00000914835, ENST00000958090, ENST00000958091, ENST00000958092

RefSeq mRNA: 7 — MANE Select: NM_001377935 NM_001304275, NM_001377935, NM_001377936, NM_001377937, NM_001377938, NM_005312, NM_198679

CCDS: CCDS48047, CCDS48048, CCDS78450, CCDS94521

Canonical transcript exons

ENST00000683357 — 27 exons

Exon	Start	End
ENSE00001457101	131603961	131604053
ENSE00001610593	131580263	131580391
ENSE00001611514	131576775	131579647
ENSE00001628621	131584518	131584596
ENSE00001637362	131596298	131596373
ENSE00001658815	131625922	131626422
ENSE00001687745	131589886	131589978
ENSE00001705266	131584311	131584412
ENSE00001740965	131630236	131630324
ENSE00001741978	131587942	131588026
ENSE00001747468	131643239	131643417
ENSE00001749893	131650810	131650949
ENSE00001770006	131588801	131588986
ENSE00001789563	131592099	131592183
ENSE00001805610	131582605	131582702
ENSE00001806452	131650129	131650242
ENSE00002702363	131598199	131598310
ENSE00002706655	131602061	131602149
ENSE00003519010	131629102	131629254
ENSE00003531518	131638635	131638791
ENSE00003563502	131628549	131628672
ENSE00003610028	131627913	131628096
ENSE00003789204	131587736	131587830
ENSE00003918135	131739770	131740076
ENSE00003921075	131619051	131619206
ENSE00003993064	131604931	131605188
ENSE00003993070	131621796	131621998

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.0352 / max 429.0684, expressed in 1805 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102876	9.0273	1748
102875	7.8991	1661
102851	3.2655	1220
102866	0.2806	126
102852	0.1678	51
102837	0.1255	51
102874	0.1009	28
102867	0.0908	44
102865	0.0777	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.61	gold quality
cortical plate	UBERON:0005343	96.96	gold quality
muscle of leg	UBERON:0001383	96.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.73	gold quality
apex of heart	UBERON:0002098	95.66	gold quality
sural nerve	UBERON:0015488	95.48	gold quality
granulocyte	CL:0000094	94.80	gold quality
nucleus accumbens	UBERON:0001882	94.11	gold quality
right lung	UBERON:0002167	93.34	gold quality
right frontal lobe	UBERON:0002810	93.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.13	gold quality
caudate nucleus	UBERON:0001873	92.78	gold quality
colonic epithelium	UBERON:0000397	92.66	gold quality
monocyte	CL:0000576	92.65	gold quality
cerebellar hemisphere	UBERON:0002245	92.58	gold quality
leukocyte	CL:0000738	92.49	gold quality
cerebellar cortex	UBERON:0002129	92.45	gold quality
heart left ventricle	UBERON:0002084	92.44	gold quality
mononuclear cell	CL:0000842	92.26	gold quality
lymph node	UBERON:0000029	92.26	gold quality
prefrontal cortex	UBERON:0000451	92.26	gold quality
upper lobe of left lung	UBERON:0008952	92.13	gold quality
putamen	UBERON:0001874	92.08	gold quality
cardiac ventricle	UBERON:0002082	91.96	gold quality
ganglionic eminence	UBERON:0004023	91.72	gold quality
amygdala	UBERON:0001876	91.55	gold quality
upper lobe of lung	UBERON:0008948	91.50	gold quality
cingulate cortex	UBERON:0003027	91.21	gold quality
right atrium auricular region	UBERON:0006631	91.18	gold quality
muscle organ	UBERON:0001630	91.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	2027.91
E-GEOD-180759	yes	1835.56
E-HCAD-25	yes	614.52
E-ANND-3	yes	13.52
E-CURD-119	yes	7.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

128 targeting RAPGEF1, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AC	99.84	70.77	4351

Literature-anchored findings (GeneRIF, showing 29)

• Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells. (PMID:12697763)
• C3G and Hck interact physically and functionally in vivo to activate kinase-dependent and caspase-mediated apoptosis, which is independent of catalytic domain of C3G (PMID:14551197)
• C3G interferes with at least two separate aspects of oncogenic transformation - cell cycle progression and loss of contact inhibition. (PMID:15077165)
• amplification and increased expression of the C3G gene may play some role in human lung carcinogenesis through derangement of the CRK-Rap1 signaling pathway (PMID:15138850)
• Src family kinases or pervanadate treatment induces phosphorylation of C3G on Y504. Unlike C3G, which is mostly cytosolic, pY504C3G locates to the Golgi & subcortical actin cytoskeleton, providing evidence for a function for C3G at these compartments. (PMID:15320955)
• Inactivation of Crk SH3 domain-binding guanine nucleotide-releasing factor is associated with cervical squamous cell carcinoma (PMID:16681758)
• C3G triggers PP2A activation and binding to MEK and ERK at the subcortical actin cytoskeleton, thus favouring ERK dephosphorylation. (PMID:17825818)
• Results identify a mechanism by which the WAVE2 complex regulates T cell receptor signaling to Rap1 and integrin activation via Abl- and CrkL-C3G. (PMID:18809728)
• Rap1 and its exchange factor C3G in mediating Fc gammaR-dependent phagocytosis. (PMID:18832707)
• Genetic polymorphisms in the RAPGEF1 gene and positive association between one polymorphism and type 2 diabetes in the Korean population. (PMID:19297053)
• These results strongly suggest a dual regulatory role for C3G in chronic myeloid leukemia cells, modulating both apoptosis and survival via Rap-dependent and independent mechanisms. (PMID:19324082)
• ALK activation of Rap1 via the Rap1-specific GEF C3Gmay contribute to cell proliferation and oncogenesis of neuroblastoma. (PMID:20190816)
• significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder (PMID:20436929)
• C3G as a novel target of c-Abl (PMID:20581864)
• Data demonstrated that the polymorphism in TP53 (rs1042522) was associated with type 2 diabetes, and that potential interaction of TP53 (rs1042522) and RAPGEF1 (rs11243444), or NRF1 (rs1882095) increased the risk of type 2 diabetes. (PMID:21146886)
• C3G overexpression induces neurite-like extensions in MDA-MB-231 and BT549 breast carcinoma cells and not in a variety of other cancer cell lines examined. (PMID:21223981)
• found somatic demethylation of a relaxed-criterion CpG island (CGI-B) located in the first intron of RAPGEF1 in 40% of colon cancers and 8% of gastric cancers relative to their matching normal tissues that were always methylated (PMID:21399874)
• Lyn controls spatial activation of Rap1 by recruiting the CrkL-C3G protein complex to the leading edge (PMID:21628423)
• The possibility of cellular phospho-C3G (pC3G) being a substrate of the intracellular T-cell protein tyrosine phosphatase TC-PTP (PTPN2) using the human neuroblastoma cell line, was studied. (PMID:21876762)
• C3G plays an important role in platelet clotting through a mechanism involving its GEF activity and suggest that it might be also involved in neutrophil development. (PMID:22659131)
• C3G/RAP1 activity is involved in the metastatic spread of epithelial ovarian cancer. (PMID:25617801)
• our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis. (PMID:27286263)
• C3G plays a significant role in different steps of megakaryopoiesis (PMID:30567575)
• C3G localizes to the mother centriole in a cenexin-dependent manner and regulates centrosome duplication and primary cilium length. (PMID:32371504)
• Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas. (PMID:32873726)
• Complex formation and reciprocal regulation between GSK3beta and C3G. (PMID:33450305)
• Zebrafish modeling mimics developmental phenotype of patients with RAPGEF1 mutation. (PMID:33834495)
• Experimental Characterization of the Interaction between the N-Terminal SH3 Domain of Crkl and C3G. (PMID:34947971)
• Identification and functional validation of SRC and RAPGEF1 as new direct targets of miR-203, involved in regulation of epidermal homeostasis. (PMID:37635193)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rapgef1b	ENSDARG00000015971
danio_rerio	rapgef1a	ENSDARG00000043593
mus_musculus	Rapgef1	ENSMUSG00000039844
rattus_norvegicus	Rapgef1	ENSRNOG00000014316
drosophila_melanogaster	C3G	FBGN0259228
caenorhabditis_elegans		WBGENE00021320

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Rap guanine nucleotide exchange factor 1 — Q13905 (reviewed: Q13905)

Alternative names: CRK SH3-binding GNRP, Guanine nucleotide-releasing factor 2, Protein C3G

All UniProt accessions (4): Q13905, A0A804HL87, H0Y6R4, Q5JUE9

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-releasing protein that binds to SH3 domain of CRK and GRB2/ASH. Transduces signals from CRK to activate RAS. Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1. Plays a role in the establishment of basal endothelial barrier function. Plays a role in nerve growth factor (NGF)-induced sustained activation of Rap1 and neurite outgrowth.

Subunit / interactions. Interacts with HCK (via SH3-binding sites). Interacts with CRK (via SH3-binding sites).

Subcellular location. Early endosome.

Tissue specificity. Ubiquitously expressed in adult and fetus. Expression is high in adult skeletal muscle and placenta and in fetal brain and heart. Low levels of expression in adult and fetal liver.

Post-translational modifications. Phosphorylation at Tyr-504 enhances activity as Rap guanine nucleotide exchange factor.

Isoforms (4)

UniProt ID	Names	Canonical?
Q13905-1	Long	yes
Q13905-2	Short
Q13905-3	3
Q13905-4	4

RefSeq proteins (7): NP_001291204, NP_001364864, NP_001364865, NP_001364866, NP_001364867, NP_005303, NP_941372 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR008937	Ras-like_GEF	Family
IPR019804	Ras_G-nucl-exch_fac_CS	Conserved_site
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00617, PF00618

UniProt features (38 total): sequence conflict 9, modified residue 6, compositionally biased region 5, region of interest 5, short sequence motif 4, splice variant 3, domain 2, chain 1, sequence variant 1, mutagenesis site 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5L23	X-RAY DIFFRACTION	1.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13905-F1	65.21	0.36

Functional residue map

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

Post-translational modifications (7): 281, 293, 314, 335, 360, 504, 57

Mutagenesis-validated functional residues (1):

Position	Phenotype
504	abolishes phosphorylation by hck.

Function

Pathways and Gene Ontology

Reactome pathways

23 pathways

ID	Pathway
R-HSA-170968	Frs2-mediated activation
R-HSA-186763	Downstream signal transduction
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9027284	Erythropoietin activates RAS
R-HSA-912631	Regulation of signaling by CBL
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-168256	Immune System
R-HSA-169893	Prolonged ERK activation events
R-HSA-186797	Signaling by PDGF
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-187687	Signalling to ERKs
R-HSA-194315	Signaling by Rho GTPases
R-HSA-449147	Signaling by Interleukins
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-6806834	Signaling by MET
R-HSA-8875878	MET promotes cell motility
R-HSA-9006335	Signaling by Erythropoietin
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 249 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_RESPONSE_TO_NERVE_GROWTH_FACTOR, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY

GO Biological Process (29): signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), Ras protein signal transduction (GO:0007265), nervous system development (GO:0007399), positive regulation of neuron projection development (GO:0010976), Rap protein signal transduction (GO:0032486), nerve growth factor signaling pathway (GO:0038180), positive regulation of GTPase activity (GO:0043547), establishment of endothelial barrier (GO:0061028), cellular response to cAMP (GO:0071320), regulation of cell junction assembly (GO:1901888), cellular response to nerve growth factor stimulus (GO:1990090), blood vessel development (GO:0001568), small GTPase-mediated signal transduction (GO:0007264), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), regulation of JNK cascade (GO:0046328), negative regulation of Ras protein signal transduction (GO:0046580), platelet-derived growth factor receptor signaling pathway (GO:0048008), positive regulation of phagocytosis (GO:0050766), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), canonical Wnt signaling pathway (GO:0060070), positive regulation of Fc receptor mediated stimulatory signaling pathway (GO:0060369), neural precursor cell proliferation (GO:0061351), ERK1 and ERK2 cascade (GO:0070371), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of canonical Wnt signaling pathway (GO:0090090), cell-cell adhesion (GO:0098609), negative regulation of neural precursor cell proliferation (GO:2000178)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), SH3 domain binding (GO:0017124), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome (GO:0005768), phagocytic vesicle membrane (GO:0030670), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	3
Prolonged ERK activation events	1
Signaling by PDGF	1
MET promotes cell motility	1
RHO GTPase cycle	1
Signaling by Erythropoietin	1
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
Immune System	1
Signalling to ERKs	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Cytokine Signaling in Immune system	1
Signaling by Interleukins	1
Signaling by MET	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
small GTPase-mediated signal transduction	2
intracellular signaling cassette	2
cytoplasm	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
system development	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
endothelial cell development	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
cell junction assembly	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
cellular response to growth factor stimulus	1
response to nerve growth factor	1
vasculature development	1
anatomical structure development	1
JNK cascade	1
regulation of MAPK cascade	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1

Protein interactions and networks

STRING

1998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAPGEF1	CRK	P46108	999
RAPGEF1	CRKL	P46109	997
RAPGEF1	CBL	P22681	987
RAPGEF1	BCAR1	P56945	982
RAPGEF1	GRB2	P29354	879
RAPGEF1	RHOQ	P17081	840
RAPGEF1	DOCK1	Q14185	820
RAPGEF1	CFHR5	Q9BXR6	806
RAPGEF1	RABIF	P47224	806
RAPGEF1	PXN	P49023	802
RAPGEF1	FRS2	Q8WU20	791
RAPGEF1	SRC	P12931	764
RAPGEF1	BRAF	P15056	729
RAPGEF1	WASF2	Q9Y6W5	724
RAPGEF1	RAP1A	P10113	716

IntAct

45 interactions, top by confidence:

A	B	Type	Score
RAPGEF1	CRK	psi-mi:“MI:0915”(physical association)	0.810
CRK	RAPGEF1	psi-mi:“MI:0915”(physical association)	0.810
RAPGEF1	CRKL	psi-mi:“MI:0914”(association)	0.720
RAPGEF1	CRKL	psi-mi:“MI:0915”(physical association)	0.720
CRKL	RAPGEF1	psi-mi:“MI:0915”(physical association)	0.720
RAPGEF1	ABL1	psi-mi:“MI:0915”(physical association)	0.660
GRB2	RAPGEF1	psi-mi:“MI:0915”(physical association)	0.660
RAPGEF1	GRB2	psi-mi:“MI:0407”(direct interaction)	0.660
RAPGEF1	CRK	psi-mi:“MI:0915”(physical association)	0.560
EGFR	RAPGEF1	psi-mi:“MI:0915”(physical association)	0.550
RAPGEF1	EGFR	psi-mi:“MI:0915”(physical association)	0.550
CRK	ARHGAP42	psi-mi:“MI:0914”(association)	0.530
Kidins220	CRKL	psi-mi:“MI:0914”(association)	0.500
CRK	BCR/ABL fusion	psi-mi:“MI:0914”(association)	0.460
RAP1A	RAPGEF1	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF1	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
SRC	RAPGEF1	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF1	FYN	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF1	NCK1	psi-mi:“MI:0915”(physical association)	0.400
RAPGEF1	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (79): RAPGEF1 (Affinity Capture-RNA), RAPGEF1 (Affinity Capture-RNA), RAPGEF1 (Affinity Capture-Western), RAPGEF1 (Affinity Capture-Western), RAPGEF1 (Reconstituted Complex), RAPGEF1 (Biochemical Activity), RAPGEF1 (Two-hybrid), RAPGEF1 (Affinity Capture-MS), RAPGEF1 (Affinity Capture-MS), RAPGEF1 (PCA), RAPGEF1 (Affinity Capture-Luminescence), RAPGEF1 (Two-hybrid), RAPGEF1 (Affinity Capture-Western), RAP1A (Reconstituted Complex), RAP2B (Reconstituted Complex)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: A2AR50, A2CEA7, B0M0P8, B0UXH6, F1M386, F1MSG6, F1PBJ0, O14827, P27671, P28818, P70392, Q03385, Q03386, Q07889, Q07890, Q12967, Q13905, Q13972, Q3MIN7, Q3UYI5, Q4R7W3, Q54FF3, Q54PQ4, Q54TK8, Q552M5, Q55GH9, Q5JS13, Q5ZJK0, Q60695, Q86G47, Q86X27, Q8CHG7, Q8IS14, Q8IS15, Q8IS16, Q8IS18, Q8IS20, Q8IS21, Q8SSQ0, Q8SSW7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	RAPGEF1	phosphorylation
ABL1	unknown	RAPGEF1	phosphorylation
HCK	up-regulates	RAPGEF1	phosphorylation
CRK	up-regulates	RAPGEF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Downstream signal transduction	7	121.1×	3e-11
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	118.0×	7e-08
Regulation of signaling by CBL	5	112.8×	7e-08
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	5	81.1×	2e-07
Signaling by CSF1 (M-CSF) in myeloid cells	5	78.7×	2e-07
Signaling by SCF-KIT	5	56.4×	8e-07
FCGR3A-mediated phagocytosis	6	51.1×	1e-07
VEGFA-VEGFR2 Pathway	6	38.0×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of Rac protein signal transduction	5	140.9×	1e-07
ephrin receptor signaling pathway	5	74.8×	1e-06
epidermal growth factor receptor signaling pathway	5	53.9×	5e-06
positive regulation of ERK1 and ERK2 cascade	5	18.5×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	115
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

5779 predictions. Top by Δscore:

Variant	Effect	Δscore
9:131579647:CCTGG:C	acceptor_gain	1.0000
9:131580261:A:AC	donor_gain	1.0000
9:131580262:C:CC	donor_gain	1.0000
9:131580262:CG:C	donor_gain	1.0000
9:131580388:CCCC:C	acceptor_gain	1.0000
9:131580389:CCCC:C	acceptor_gain	1.0000
9:131582597:CTACT:C	donor_loss	1.0000
9:131582602:CA:C	donor_loss	1.0000
9:131582603:A:AC	donor_gain	1.0000
9:131582604:C:CA	donor_gain	1.0000
9:131582604:CA:C	donor_gain	1.0000
9:131582604:CAGG:C	donor_gain	1.0000
9:131582604:CAGGT:C	donor_gain	1.0000
9:131584306:CTCA:C	donor_loss	1.0000
9:131584307:TCAC:T	donor_loss	1.0000
9:131584308:CACC:C	donor_loss	1.0000
9:131584309:A:AC	donor_gain	1.0000
9:131584309:AC:A	donor_gain	1.0000
9:131584310:C:CT	donor_gain	1.0000
9:131584310:CC:C	donor_gain	1.0000
9:131584310:CCT:C	donor_gain	1.0000
9:131584409:AGTG:A	acceptor_gain	1.0000
9:131584410:GTG:G	acceptor_gain	1.0000
9:131584411:TG:T	acceptor_gain	1.0000
9:131584413:C:CC	acceptor_gain	1.0000
9:131584417:C:CT	acceptor_gain	1.0000
9:131584418:G:T	acceptor_gain	1.0000
9:131584592:GGACC:G	acceptor_gain	1.0000
9:131584593:GACC:G	acceptor_gain	1.0000
9:131584594:ACC:A	acceptor_gain	1.0000

AlphaMissense

8273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:131579561:A:G	L1057P	1.000
9:131579566:C:A	W1055C	1.000
9:131579566:C:G	W1055C	1.000
9:131579568:A:G	W1055R	1.000
9:131579568:A:T	W1055R	1.000
9:131579570:A:G	L1054P	1.000
9:131580298:G:C	F1016L	1.000
9:131580298:G:T	F1016L	1.000
9:131580300:A:G	F1016L	1.000
9:131580309:A:G	W1013R	1.000
9:131580309:A:T	W1013R	1.000
9:131580362:A:T	V995D	1.000
9:131580364:G:C	F994L	1.000
9:131580364:G:T	F994L	1.000
9:131580365:A:G	F994S	1.000
9:131580366:A:G	F994L	1.000
9:131580371:A:G	L992P	1.000
9:131580374:T:A	D991V	1.000
9:131580374:T:G	D991A	1.000
9:131580380:A:G	L989P	1.000
9:131580386:A:G	L987P	1.000
9:131580389:C:T	G986E	1.000
9:131580390:C:A	G986W	1.000
9:131580390:C:G	G986R	1.000
9:131580390:C:T	G986R	1.000
9:131582611:G:T	P983Q	1.000
9:131582638:A:G	L974P	1.000
9:131582647:C:G	R971P	1.000
9:131582658:G:C	F967L	1.000
9:131582658:G:T	F967L	1.000

dbSNP variants (sampled 300 via entrez): RS1000025399 (9:131666338 T>C), RS1000028046 (9:131578835 A>T), RS1000047436 (9:131707417 A>G), RS1000064386 (9:131584108 C>T), RS1000101358 (9:131695372 G>A), RS1000108422 (9:131713546 A>G), RS1000123182 (9:131665063 T>C), RS1000128530 (9:131623273 C>A,T), RS1000144706 (9:131624255 C>T), RS1000167025 (9:131678592 A>G), RS1000179837 (9:131601751 A>G), RS1000183828 (9:131628848 A>T), RS1000200728 (9:131719678 CT>C), RS1000222172 (9:131613001 C>T), RS1000227076 (9:131681381 T>C,G)

Disease associations

OMIM: gene MIM:600303 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006279_6	Cerebrospinal fluid α-synuclein levels	8.000000e-07
GCST009462_102	Optic disc size	2.000000e-13
GCST010303_62	Nevus count or cutaneous melanoma	3.000000e-09
GCST010304_68	Cutaneous malignant melanoma	2.000000e-08
GCST010396_279	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-14
GCST90016670_6	Kidney volume	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009323	alpha synuclein measurement
EFO:0004632	nevus count
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	5
Arsenic	affects methylation, increases abundance, increases expression	3
sodium arsenite	increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Lead	affects expression, increases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
dicrotophos	increases expression	1
sodium arsenate	increases abundance, increases expression	1
arsenite	affects binding, decreases reaction	1
benzo(e)pyrene	decreases methylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
beta-methylcholine	affects expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	increases expression	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
mono(carboxy-isooctyl)phthalate	affects expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	decreases expression	1
Copper	affects binding, increases expression	1
Cycloheximide	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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