RAPGEF2

Summary

RAPGEF2 (Rap guanine nucleotide exchange factor 2, HGNC:16854) is a protein-coding gene on chromosome 4q32.1, encoding Rap guanine nucleotide exchange factor 2 (Q9Y4G8). Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner.

Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000 [PubMed 10934204]).

Source: NCBI Gene 9693 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 178 total — 2 pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_001394067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16854
Approved symbol	RAPGEF2
Name	Rap guanine nucleotide exchange factor 2
Location	4q32.1
Locus type	gene with protein product
Status	Approved
Aliases	PDZ-GEF1, RA-GEF, DKFZP586O1422, KIAA0313
Ensembl gene	ENSG00000109756
Ensembl biotype	protein_coding
OMIM	609530
Entrez	9693

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 10 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000264431, ENST00000502485, ENST00000503328, ENST00000504604, ENST00000505026, ENST00000505478, ENST00000509891, ENST00000510253, ENST00000510510, ENST00000511336, ENST00000512056, ENST00000513816, ENST00000514565, ENST00000644474, ENST00000644902, ENST00000691494, ENST00000908959, ENST00000941768, ENST00000941769

RefSeq mRNA: 7 — MANE Select: NM_001394067 NM_001351724, NM_001351725, NM_001351726, NM_001351727, NM_001351728, NM_001394067, NM_014247

CCDS: CCDS43277, CCDS93662, CCDS93663

Canonical transcript exons

ENST00000691494 — 30 exons

Exon	Start	End
ENSE00000740328	159353487	159354046
ENSE00000740329	159352685	159352910
ENSE00000740330	159350137	159350289
ENSE00000740348	159343281	159343404
ENSE00000740353	159342979	159343190
ENSE00000740358	159341564	159341947
ENSE00000740360	159339114	159339354
ENSE00000740362	159338311	159338468
ENSE00000740363	159332451	159332697
ENSE00000740366	159331926	159332034
ENSE00000740368	159331630	159331833
ENSE00000740370	159331431	159331538
ENSE00000740372	159330334	159330498
ENSE00000740380	159323459	159323617
ENSE00000740388	159322347	159322483
ENSE00000813598	159355853	159356158
ENSE00000813599	159345106	159345329
ENSE00001001868	159344036	159344059
ENSE00002062206	159186642	159186712
ENSE00002062729	159193200	159193256
ENSE00002074060	159210500	159210583
ENSE00002490287	159329858	159330010
ENSE00003472115	159304342	159304473
ENSE00003472776	159238809	159238884
ENSE00003638621	159243774	159243791
ENSE00003655718	159241201	159241368
ENSE00003784708	159346789	159346998
ENSE00003789116	159314591	159314768
ENSE00003930214	159103079	159104231
ENSE00003935884	159358114	159360173

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1719 / max 741.9104, expressed in 1806 samples.

FANTOM5 promoters (30 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50346	5.1577	1663
50344	4.9290	1238
50372	3.6195	231
50347	3.0836	1284
50343	2.9340	828
50349	0.7329	283
50345	0.5344	267
50363	0.4688	158
50376	0.4181	89
50373	0.3722	101

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.21	gold quality
middle temporal gyrus	UBERON:0002771	99.08	gold quality
endothelial cell	CL:0000115	98.41	gold quality
frontal pole	UBERON:0002795	98.32	gold quality
postcentral gyrus	UBERON:0002581	98.12	gold quality
orbitofrontal cortex	UBERON:0004167	98.09	gold quality
parietal lobe	UBERON:0001872	98.05	gold quality
tibia	UBERON:0000979	97.98	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.89	gold quality
entorhinal cortex	UBERON:0002728	97.77	gold quality
superior frontal gyrus	UBERON:0002661	97.76	gold quality
trabecular bone tissue	UBERON:0002483	97.71	gold quality
choroid plexus epithelium	UBERON:0003911	97.15	gold quality
corpus callosum	UBERON:0002336	97.07	gold quality
visceral pleura	UBERON:0002401	96.65	gold quality
CA1 field of hippocampus	UBERON:0003881	96.31	gold quality
pleura	UBERON:0000977	96.14	gold quality
heart right ventricle	UBERON:0002080	96.06	gold quality
skin of hip	UBERON:0001554	96.00	gold quality
parietal pleura	UBERON:0002400	96.00	gold quality
occipital lobe	UBERON:0002021	95.99	gold quality
calcaneal tendon	UBERON:0003701	95.83	gold quality
metanephric glomerulus	UBERON:0004736	95.83	gold quality
middle frontal gyrus	UBERON:0002702	95.79	gold quality
primary visual cortex	UBERON:0002436	95.63	gold quality
renal glomerulus	UBERON:0000074	95.59	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.50	gold quality
cartilage tissue	UBERON:0002418	95.47	gold quality
upper leg skin	UBERON:0004262	95.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

202 targeting RAPGEF2, 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-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4645-5P	99.98	65.81	1284
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-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 14)

• Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase (PMID:11799111)
• PSD-95/Dlg/ZO-1 homology (PDZ)-RhoGEF was isolated from mouse brain as a plexin-B1-specific interacting protein (PMID:12196628)
• Data show that the interaction of PDZ-GEF1 with an internalized neurotrophin receptor transported to late endosomes induces sustained activation of both Rap1 and ERK and neurite outgrowth. (PMID:17724123)
• PDZ-GEF activates Rap1 under resting conditions to stabilize cell-cell junctions and maintain basal integrity (PMID:21840392)
• DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. (PMID:22422452)
• Data indicate that expression of Rapgef2 in embryonic kidney 293T cells enables cAMP-Rap1-ERK signaling. (PMID:23800469)
• JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton. (PMID:23885123)
• We report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-beta and casein kinase-1alpha and consequently degraded by the proteasome. (PMID:24290981)
• NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro. (PMID:24340059)
• local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid. (PMID:24858808)
• Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. (PMID:25189171)
• SCF(FBXW11) bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1 (PMID:25332235)
• Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2. (PMID:31171376)
• RAPGEF2 mediates oligomeric Abeta-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer’s disease. (PMID:33345400)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rapgef2b	ENSDARG00000005482
mus_musculus	Rapgef2	ENSMUSG00000062232
rattus_norvegicus	Rapgef2	ENSRNOG00000021581

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), 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 2 — Q9Y4G8 (reviewed: Q9Y4G8)

Alternative names: Cyclic nucleotide ras GEF, Neural RAP guanine nucleotide exchange protein, PDZ domain-containing guanine nucleotide exchange factor 1, RA-GEF-1, Ras/Rap1-associating GEF-1

All UniProt accessions (6): Q9Y4G8, A0A2R8Y661, A0A2R8YGD3, A0A994J7S7, D6RAK0, D6RC78

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Also acts as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP or not. Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Also provides inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brain-derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions.

Subunit / interactions. Interacts with CDH1, CTNNB1 and TJP1. Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains); the interaction occurs before or after NGF stimulation. Interacts with KIDINS220 and NTRK1; the interactions occur after NGF stimulation. Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a neuronal growth factor (NGF)-dependent manner. Interacts (via C-terminal domain) with NEDD4 (via WW domains); this interaction leads to ubiquitination and degradation via the proteasome pathway in a cAMP-independent manner. Interacts with MAGI1 isoform 3 (via PDZ domain). Interacts with ADRB1 (via C-terminal PDZ motif); the interaction is direct. Interacts (via Ras-associating domain) with RAP1A (via GTP-bound active form). Interacts weakly with HRAS (via GDP- and GTP-bound forms). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains).

Subcellular location. Cytoplasm. Perinuclear region. Cell membrane. Late endosome. Cell junction.

Tissue specificity. Expressed in primary neuronal and endocrine cells (at protein level). Highest expression levels in brain. Lower expression levels in heart, kidney, lung, placenta and blood leukocytes.

Post-translational modifications. Ubiquitinated by NEDD4, leading to proteasomal degradation. Phosphorylation by PLK2 promotes its activity.

Disease relevance. Epilepsy, familial adult myoclonic, 7 (FAME7) [MIM:618075] A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME7 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Ras-associating domain is necessary for the Rap guanine nucleotide exchange activity. The N-terminal regionis necessary for cAMP-binding. The PDZ domain is necessary for its targeting to the cell membrane.

Similarity. Belongs to the RAPGEF2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4G8-1	1	yes
Q9Y4G8-2	2

RefSeq proteins (7): NP_001338653, NP_001338654, NP_001338655, NP_001338656, NP_001338657, NP_001380996, NP_055062 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR000595	cNMP-bd_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001478	PDZ	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00595, PF00617, PF00618, PF00788

UniProt features (43 total): modified residue 13, compositionally biased region 9, mutagenesis site 8, region of interest 6, domain 4, chain 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6QDT	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4G8-F1	60.40	0.25

Functional residue map

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

Ligand- & substrate-binding residues (1): 135–254

Post-translational modifications (13): 501, 644, 806, 930, 933, 1022, 1080, 1089, 1095, 1116, 1120, 1159, 1176

Mutagenesis-validated functional residues (8):

Position	Phenotype
211	abolishes camp-binding.
215	does not abolish camp-binding.
396–399	loss of cell membrane targeting.
606–626	abolishes interaction with rap1a gtp-bound form and translocation from the cytoplasm to the perinuclear region. does not
898	does not inhibit interaction with nedd4. does not interact with hras. reduces ubiquitination.
1406	abolishes interaction with nedd4 and nedd4-induced ubiquitination and degradation; when associated with a-1428.
1428	abolishes interaction with nedd4 and nedd4-induced ubiquitination and degradation; when associated with a-1406.
1497–1499	no loss of cell membrane targeting.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-162582	Signal Transduction
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling

MSigDB gene sets: 473 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_BINDING, chr4q32, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS

GO Biological Process (43): MAPK cascade (GO:0000165), blood vessel development (GO:0001568), neuron migration (GO:0001764), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), neuropeptide signaling pathway (GO:0007218), small GTPase-mediated signal transduction (GO:0007264), Ras protein signal transduction (GO:0007265), negative regulation of cell population proliferation (GO:0008285), positive regulation of neuron projection development (GO:0010976), ventricular system development (GO:0021591), forebrain neuron development (GO:0021884), microvillus assembly (GO:0030033), neuron projection development (GO:0031175), brain-derived neurotrophic factor receptor signaling pathway (GO:0031547), positive regulation of protein binding (GO:0032092), Rap protein signal transduction (GO:0032486), intracellular signal transduction (GO:0035556), nerve growth factor signaling pathway (GO:0038180), positive regulation of GTPase activity (GO:0043547), positive regulation of protein kinase activity (GO:0045860), negative regulation of melanin biosynthetic process (GO:0048022), regulation of synaptic plasticity (GO:0048167), negative regulation of dendrite morphogenesis (GO:0050774), establishment of endothelial barrier (GO:0061028), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to cAMP (GO:0071320), cellular response to cGMP (GO:0071321), adenylate cyclase-activating adrenergic receptor signaling pathway (GO:0071880), protein localization to plasma membrane (GO:0072659), establishment of endothelial intestinal barrier (GO:0090557), regulation of cell junction assembly (GO:1901888), positive regulation of microvillus assembly (GO:1903698), cellular response to nerve growth factor stimulus (GO:1990090), positive regulation of cAMP-dependent protein kinase activity (GO:2000481), positive regulation of dendritic cell apoptotic process (GO:2000670), positive regulation of vasculogenesis (GO:2001214), positive regulation of neuron migration (GO:2001224), signal transduction (GO:0007165), nervous system development (GO:0007399)

GO Molecular Function (10): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), calcium ion binding (GO:0005509), diacylglycerol binding (GO:0019992), PDZ domain binding (GO:0030165), cAMP binding (GO:0030552), beta-1 adrenergic receptor binding (GO:0031697), WW domain binding (GO:0050699), phosphatidic acid binding (GO:0070300), protein binding (GO:0005515)

GO Cellular Component (16): cytoplasm (GO:0005737), late endosome (GO:0005770), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), membrane (GO:0016020), apical plasma membrane (GO:0016324), endocytic vesicle (GO:0030139), protein-containing complex (GO:0032991), neuron projection (GO:0043005), neuronal cell body (GO:0043025), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), endosome (GO:0005768), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
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	4
intracellular signaling cassette	2
signal transduction	2
G protein-coupled receptor signaling pathway	2
small GTPase-mediated signal transduction	2
intracellular anatomical structure	2
GTPase activity	2
GTPase regulator activity	2
protein domain specific binding	2
anion binding	2
cytoplasm	2
cytoplasmic vesicle	2
cell junction	2
vasculature development	1
anatomical structure development	1
cell migration	1
generation of neurons	1
G protein-coupled receptor activity	1
adenylate cyclase activity	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
brain development	1
system development	1
forebrain neuron differentiation	1
central nervous system neuron development	1
microvillus organization	1
plasma membrane bounded cell projection assembly	1
neuron development	1
plasma membrane bounded cell projection organization	1
cell surface receptor protein tyrosine kinase signaling pathway	1
protein binding	1
regulation of protein binding	1
positive regulation of binding	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
regulation of GTPase activity	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAPGEF2	RAP1A	P10113	895
RAPGEF2	RAP2A	P10114	874
RAPGEF2	MAGI2	Q86UL8	861
RAPGEF2	RAP1B	P09526	860
RAPGEF2	TJP2	Q9UDY2	812
RAPGEF2	SAMD12	Q8N8I0	758
RAPGEF2	MAGI1	Q96QZ7	751
RAPGEF2	MRAS	O14807	744
RAPGEF2	RAP2B	P17964	735
RAPGEF2	AFDN	P55196	674
RAPGEF2	STARD7	Q9NQZ5	645
RAPGEF2	RAP2C	Q9Y3L5	629
RAPGEF2	NTRK1	P04629	622
RAPGEF2	TJP1	Q07157	603
RAPGEF2	CTNNB1	P35222	595

IntAct

167 interactions, top by confidence:

A	B	Type	Score
YAP1	MPDZ	psi-mi:“MI:0914”(association)	0.780
RAPGEF2	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.670
MAGI2	RAPGEF2	psi-mi:“MI:0407”(direct interaction)	0.670
MAGI2	RAPGEF2	psi-mi:“MI:0915”(physical association)	0.670
RAPGEF2	MAGI2	psi-mi:“MI:0915”(physical association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
RAPGEF6	RAPGEF2	psi-mi:“MI:0915”(physical association)	0.610
RAPGEF2	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.610
RAPGEF2	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.610
MAGI1	RAPGEF2	psi-mi:“MI:0915”(physical association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
RAPGEF2	YWHAZ	psi-mi:“MI:0915”(physical association)	0.560
PRKCI	NIPSNAP2	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YAP1	CCDC85C	psi-mi:“MI:0914”(association)	0.530
RAPGEF2	MAGI1	psi-mi:“MI:0915”(physical association)	0.520
RAPGEF2	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF2	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (110): RAPGEF2 (Affinity Capture-Western), RAPGEF2 (Affinity Capture-Western), BTRC (Affinity Capture-Western), RAPGEF2 (Co-localization), RAPGEF2 (Co-localization), UBC (Affinity Capture-Western), FBXW11 (Affinity Capture-Western), EPB41L5 (Affinity Capture-MS), KIF11 (Affinity Capture-MS), PTPN13 (Affinity Capture-MS), FLNC (Affinity Capture-MS), LMNA (Affinity Capture-MS), SCYL2 (Affinity Capture-MS), HIST2H4B (Affinity Capture-MS), MAGI1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: A0JM95, A4IFE4, F1M386, F1MSG6, F1PBJ0, Q0VAM2, Q28EC1, Q5RC04, Q6DBW1, Q6DHR3, Q8CHG7, Q8IS18, Q8IS19, Q8JZL7, Q8MVR1, Q8N431, Q8N9B8, Q95KH6, Q9D300, Q9Y4G8, A2AR50, A2CEA7, B0M0P8, B0UXH6, O14827, P27671, P28818, P70392, Q03385, Q03386, Q07889, Q07890, Q12967, Q13905, Q13972, Q3MIN7, Q3UYI5, Q4R7W3, Q54FF3, Q54PQ4

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
PRKCQ	up-regulates	RAPGEF2	phosphorylation
CSNK1A1	“down-regulates quantity by destabilization”	RAPGEF2	phosphorylation
SCF-betaTRCP	“down-regulates quantity by destabilization”	RAPGEF2	ubiquitination
RAPGEF2	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
CDK5	“up-regulates activity”	RAPGEF2	phosphorylation
NEDD4	“down-regulates quantity”	RAPGEF2	ubiquitination
IKBKB	“down-regulates quantity by destabilization”	RAPGEF2	phosphorylation
PLK2	“up-regulates activity”	RAPGEF2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 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
Activation of BAD and translocation to mitochondria	6	54.4×	7e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	48.0×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	48.0×	1e-07
Ras activation upon Ca2+ influx through NMDA receptor	6	40.8×	2e-07
Activation of BH3-only proteins	6	35.5×	5e-07
Signaling by Hippo	5	32.4×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	32.4×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	32.4×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	56.6×	2e-14
protein localization to synapse	6	40.7×	1e-06
receptor clustering	7	38.7×	2e-07
synaptic vesicle transport	5	37.3×	2e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	7	30.7×	6e-07
establishment of cell polarity	6	20.3×	4e-05
protein targeting	6	19.4×	4e-05
protein-containing complex assembly	9	9.1×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	127
Likely benign	13
Benign	14

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1180544	GRCh37/hg19 4q28.3-32.3(chr4:131303317-168722402)x3	Pathogenic
559389	RAPGEF2, 5-BP INS, TTTCA(n) REPEAT EXPANSION	Pathogenic

SpliceAI

3168 predictions. Top by Δscore:

Variant	Effect	Δscore
4:159304469:ACCAG:A	donor_loss	1.0000
4:159304470:CCAGG:C	donor_loss	1.0000
4:159304471:CAGGT:C	donor_loss	1.0000
4:159304472:AGGT:A	donor_loss	1.0000
4:159304474:G:GA	donor_loss	1.0000
4:159304475:T:G	donor_loss	1.0000
4:159314576:T:TA	acceptor_gain	1.0000
4:159314578:T:TA	acceptor_gain	1.0000
4:159314580:T:TA	acceptor_gain	1.0000
4:159314582:T:TA	acceptor_gain	1.0000
4:159314588:A:AG	acceptor_gain	1.0000
4:159314588:AAG:A	acceptor_gain	1.0000
4:159314589:A:G	acceptor_gain	1.0000
4:159314590:G:A	acceptor_gain	1.0000
4:159314590:G:GC	acceptor_loss	1.0000
4:159314590:G:GG	acceptor_gain	1.0000
4:159314765:ATTGG:A	donor_loss	1.0000
4:159314766:TTGG:T	donor_loss	1.0000
4:159314768:GGTAA:G	donor_loss	1.0000
4:159314769:G:GG	donor_gain	1.0000
4:159314769:GTAAG:G	donor_loss	1.0000
4:159314770:T:TC	donor_loss	1.0000
4:159322343:TCA:T	acceptor_loss	1.0000
4:159322344:CAG:C	acceptor_loss	1.0000
4:159322345:A:AG	acceptor_gain	1.0000
4:159322345:AGA:A	acceptor_loss	1.0000
4:159322346:G:A	acceptor_loss	1.0000
4:159322346:G:GG	acceptor_gain	1.0000
4:159322346:GA:G	acceptor_gain	1.0000
4:159322346:GAA:G	acceptor_gain	1.0000

AlphaMissense

10996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:159314730:T:A	L111Q	1.000
4:159314730:T:C	L111P	1.000
4:159314730:T:G	L111R	1.000
4:159314751:G:C	R118P	1.000
4:159322353:T:C	L126P	1.000
4:159322380:C:A	A135D	1.000
4:159322383:T:C	F136S	1.000
4:159322416:T:C	L147P	1.000
4:159322418:T:C	C148R	1.000
4:159322419:G:A	C148Y	1.000
4:159322420:T:G	C148W	1.000
4:159322428:T:G	M151R	1.000
4:159322433:T:C	F153L	1.000
4:159322434:T:C	F153S	1.000
4:159322435:C:A	F153L	1.000
4:159322435:C:G	F153L	1.000
4:159322436:G:C	A154P	1.000
4:159322464:T:A	V163E	1.000
4:159322467:T:C	L164S	1.000
4:159323460:T:C	L170P	1.000
4:159323463:A:T	D171V	1.000
4:159323465:T:C	S172P	1.000
4:159323468:T:A	W173R	1.000
4:159323468:T:C	W173R	1.000
4:159323469:G:C	W173S	1.000
4:159323470:G:C	W173C	1.000
4:159323470:G:T	W173C	1.000
4:159323471:T:C	S174P	1.000
4:159323475:T:A	V175E	1.000
4:159323478:T:A	I176N	1.000

dbSNP variants (sampled 300 via entrez): RS1000005919 (4:159359898 T>A,G), RS1000011948 (4:159287788 T>C), RS1000042434 (4:159266141 G>A), RS10000448 (4:159198185 A>C), RS1000071328 (4:159113977 A>C,G), RS10000931 (4:159286433 C>G), RS1000096166 (4:159173717 T>C), RS1000097512 (4:159119736 G>A), RS1000103125 (4:159229498 GT>G), RS1000105417 (4:159310219 C>G), RS1000128129 (4:159159072 G>T), RS1000130309 (4:159110448 G>A), RS10001339 (4:159161504 G>A,C,T), RS1000138105 (4:159323705 A>G), RS1000138638 (4:159209064 G>A)

Disease associations

OMIM: gene MIM:609530 | disease phenotypes: MIM:618075

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	Autosomal dominant
epilepsy, familial adult myoclonic, 7	Limited	Autosomal dominant

Mondo (2): epilepsy, familial adult myoclonic, 7 (MONDO:0054847), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (0):

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001336	Myoclonus
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002353	EEG abnormality
HP:0002378	Hand tremor
HP:0003581	Adult onset
HP:0007359	Focal-onset seizure
HP:0033054	Myoclonic tremor
HP:0100576	Amaurosis fugax

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002937_9	Molybdenum levels	3.000000e-06
GCST006616_1	Uterine fibroid number (single vs multiple)	2.000000e-07
GCST010599_5	Dietary fat liking	8.000000e-06
GCST010796_5235	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009410	uterine fibroid measurement
EFO:0010816	dietary fat liking measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Valproic Acid	affects expression, decreases expression, decreases methylation	4
potassium chromate(VI)	affects cotreatment, decreases expression	2
Copper	affects binding, increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
Particulate Matter	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
coumarin	affects phosphorylation	1
hydroquinone	affects cotreatment, affects expression, affects reaction	1
triacsin C	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	increases expression, affects cotreatment	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7HA	Ubigene HEK293T RAPGEF2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS