RABGEF1

Summary

RABGEF1 (RAB guanine nucleotide exchange factor 1, HGNC:17676) is a protein-coding gene on chromosome 7q11.21, encoding Rab5 GDP/GTP exchange factor (Q9UJ41). Acts as a guanine-nucleotide releasing factor (GEF) for RAB5A by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP. It is a selective cancer dependency (DepMap: 10.2% of cell lines).

RABGEF1 forms a complex with rabaptin-5 (RABPT5; MIM 603616) that is required for endocytic membrane fusion, and it serves as a specific guanine nucleotide exchange factor (GEF) for RAB5 (RAB5A; MIM 179512) (Horiuchi et al., 1997 [PubMed 9323142]).

Source: NCBI Gene 27342 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 63 total
• Cancer dependency (DepMap): dependent in 10.2% of screened cell lines
• MANE Select transcript: NM_014504

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17676
Approved symbol	RABGEF1
Name	RAB guanine nucleotide exchange factor 1
Location	7q11.21
Locus type	gene with protein product
Status	Approved
Aliases	rabex-5, RABEX5
Ensembl gene	ENSG00000154710
Ensembl biotype	protein_coding
OMIM	609700
Entrez	27342

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 41 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000284957, ENST00000439720, ENST00000442563, ENST00000450873, ENST00000461017, ENST00000484547, ENST00000607882, ENST00000901854, ENST00000901855, ENST00000901856, ENST00000901857, ENST00000901858, ENST00000901859, ENST00000901860, ENST00000901861, ENST00000901862, ENST00000901863, ENST00000901864, ENST00000901865, ENST00000901866, ENST00000901867, ENST00000901868, ENST00000901869, ENST00000901870, ENST00000901871, ENST00000901872, ENST00000901873, ENST00000913863, ENST00000913864, ENST00000913865, ENST00000913866, ENST00000913867, ENST00000913868, ENST00000913869, ENST00000913870, ENST00000961368, ENST00000961369, ENST00000961370, ENST00000961371, ENST00000961372, ENST00000961373, ENST00000961374, ENST00000961375, ENST00000961376

RefSeq mRNA: 39 — MANE Select: NM_014504 NM_001287060, NM_001287061, NM_001287062, NM_001367722, NM_001367723, NM_001367724, NM_001367725, NM_001367726, NM_001367727, NM_001367728, NM_001367729, NM_001367730, NM_001367731, NM_001367732, NM_001367733, NM_001367734, NM_001367735, NM_001367736, NM_001367737, NM_001367738, NM_001367739, NM_001367740, NM_001367741, NM_001367742, NM_001367743, NM_001367744, NM_001367745, NM_001367746, NM_001367747, NM_001367748, NM_001367749, NM_001367750, NM_001367751, NM_001367752, NM_001367753, NM_001367754, NM_001367755, NM_001367756, NM_014504

CCDS: CCDS5535

Canonical transcript exons

ENST00000284957 — 9 exons

Exon	Start	End
ENSE00002205817	66808886	66811464
ENSE00003532587	66775227	66775393
ENSE00003626521	66795511	66795592
ENSE00003668197	66740733	66740792
ENSE00003723317	66783675	66783841
ENSE00003731045	66771883	66772078
ENSE00003820005	66805140	66805396
ENSE00003827420	66797374	66797506
ENSE00003827941	66799323	66799414

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 93.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.0536 / max 963.0420, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78884	14.9786	1786
78877	8.7632	1775
78880	5.7242	1648
78883	3.9140	1611
78879	2.1024	1209
78881	0.5711	303

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	93.38	gold quality
lower esophagus mucosa	UBERON:0035834	93.06	gold quality
skin of leg	UBERON:0001511	92.20	gold quality
zone of skin	UBERON:0000014	91.78	gold quality
stromal cell of endometrium	CL:0002255	91.21	gold quality
skin of abdomen	UBERON:0001416	91.20	gold quality
mucosa of stomach	UBERON:0001199	91.09	gold quality
esophagus mucosa	UBERON:0002469	90.79	gold quality
popliteal artery	UBERON:0002250	90.76	gold quality
tibial artery	UBERON:0007610	90.76	gold quality
blood	UBERON:0000178	90.68	gold quality
vagina	UBERON:0000996	90.63	gold quality
superior frontal gyrus	UBERON:0002661	90.60	gold quality
bone marrow cell	CL:0002092	90.31	gold quality
esophagus	UBERON:0001043	90.29	gold quality
right coronary artery	UBERON:0001625	90.23	gold quality
ectocervix	UBERON:0012249	90.22	gold quality
left adrenal gland cortex	UBERON:0035825	90.09	gold quality
left adrenal gland	UBERON:0001234	89.86	gold quality
right adrenal gland cortex	UBERON:0035827	89.84	gold quality
urinary bladder	UBERON:0001255	89.83	gold quality
corpus callosum	UBERON:0002336	89.78	gold quality
lower esophagus	UBERON:0013473	89.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.76	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.74	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.73	gold quality
descending thoracic aorta	UBERON:0002345	89.72	gold quality
left testis	UBERON:0004533	89.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.62	gold quality
right adrenal gland	UBERON:0001233	89.60	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.58
E-MTAB-5061	no	3.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting RABGEF1, 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-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
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-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 22)

• GGAs, a family of Arf-dependent clathrin adaptors involved in selection of TGN cargo, interact with the Rabaptin-5-Rabex-5 complex, a Rab4/Rab5 effector regulating endosome fusion (PMID:12505986)
• Here, we report that Rabex-5, a guanine nucleotide exchange factor for Rab5, binds to ubiquitin through two independent ubiquitin binding domains (PMID:16499958)
• Fc epsilon RI-mediated mast cell functional activation is dependent on RabGEF1’s GEF activity (PMID:17341663)
• crystal structure of the RABEX-5 catalytic core in complex with nucleotide-free RAB21, a key intermediate in the exchange reaction pathway (PMID:17450153)
• Integration of TGFB and RAS signaling silences RABGEF1 and enhances growth factor-directed cell migration. (PMID:18160707)
• functions as an E3 ligase for Ras (PMID:20655225)
• RABEX-5 and RAB5 may be involved in the development of breast cancer metastasis. (PMID:21500550)
• a novel mechanistic insight into how Rabex-5 regulates internalization and postendocytic trafficking of ubiquitinated L1 destined for lysosomal degradation. (PMID:22846990)
• KCa2.3 is localized to a caveolin-rich domain within the plasma membrane and is endocytosed in a dynamin- and Rab5-dependent manner. (PMID:22952906)
• Interaction of Rabex-5 with Rab5 depends on interaction of the MIU domain with the ubiquitinated L1 to drive its internalization. (PMID:23048039)
• This implies that Rap regulates endothelial barrier function by dual control of cytoskeletal tension. The molecular details of the signaling pathways are becoming to be elucidated (PMID:24714377)
• RABEX-5 mRNA expression is a strong predictor of poor prognosis in prostate cancer patients treated by radical prostatectomy. (PMID:24716822)
• analysis of Rabex-5 GEF activation by Rabaptin-5 (PMID:24957337)
• Expression of RABEX-5 is significantly higher in gastric cancer tissues and is associated with tumor size and lymph node metastasis. (PMID:25427001)
• RABEX-5 is a potential useful indicator and predicts a poor long-term prognosis for small cell lung cancer(SCLC), which should be considered in defining the prognosis with other well-known prognosticators in C-SCLC patients (PMID:26002576)
• The results contradict the model of feedback activation of Rab5 and instead indicate that Rbpt5 is recruited by both Rabex5 recognizing ubiquitylated cargo and by Rab4 to activate Rab5 in a feed-forward manner. (PMID:26430212)
• we identify Rabex-5 as a Immunomodulatory drugs (IMiDs) target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs. (PMID:27601648)
• RABGEF1 mediates recycling endosome fusion with GAS-containing autophagosome-like vacuoles through the STX6-VAMP3-VTI1B complex; SNAREs are involved in autophagosome formation in response to bacterial infection (PMID:27791468)
• findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function (PMID:27820702)
• RABEX-5 mRNA expression was significantly upregulated in colorectal cancer tissues. (PMID:28617553)
• The authors demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. (PMID:29360040)
• RabGEF1 functions as an oncogene in U251 glioblastoma cells and is involved in regulating AKT and Erk pathways. (PMID:33166495)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rabgef1	ENSDARG00000014430
mus_musculus	Rabgef1	ENSMUSG00000025340
rattus_norvegicus	Rabgef1	ENSRNOG00000000895
drosophila_melanogaster	Rabex-5	FBGN0262937
caenorhabditis_elegans		WBGENE00012644

Paralogs (6): VPS9D1 (ENSG00000075399), RIN3 (ENSG00000100599), RIN2 (ENSG00000132669), GAPVD1 (ENSG00000165219), RIN1 (ENSG00000174791), RINL (ENSG00000187994)

Protein

Protein identifiers

Rab5 GDP/GTP exchange factor — Q9UJ41 (reviewed: Q9UJ41)

Alternative names: RAP1, Rabaptin-5-associated exchange factor for Rab5, Rabex-5

All UniProt accessions (5): Q9UJ41, A0A1W2PPY0, C9JDA2, E9PFK9, V9GYI8

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine-nucleotide releasing factor (GEF) for RAB5A by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP. Forms a complex with RABEP1 that acts as Rab4/Rab5 effector regulating endosome fusion. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Also functions as a ubiquitin ligase.

Subunit / interactions. Interacts with RGS14; the interaction is GTP-dependent. Heterodimer with RABEP1. The heterodimer binds RAB4A and RAB5A that have been activated by GTP-binding. Interacts with RAB21, and with 100-fold lower affinity also with RAB22. Binds TSC2, GGA1, GGA2, GGA3, AP1G1 and AP1G2. Interacts with ubiquitinated EGFR.

Subcellular location. Cytoplasm. Early endosome. Recycling endosome.

Post-translational modifications. Monoubiquitinated.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UJ41-2	1	yes
Q9UJ41-3	2, Long
Q9UJ41-4	3

RefSeq proteins (39): NP_001273989, NP_001273990, NP_001273991, NP_001354651, NP_001354652, NP_001354653, NP_001354654, NP_001354655, NP_001354656, NP_001354657, NP_001354658, NP_001354659, NP_001354660, NP_001354661, NP_001354662, NP_001354663, NP_001354664, NP_001354665, NP_001354666, NP_001354667, NP_001354668, NP_001354669, NP_001354670, NP_001354671, NP_001354672, NP_001354673, NP_001354674, NP_001354675, NP_001354676, NP_001354677, NP_001354678, NP_001354679, NP_001354680, NP_001354681, NP_001354682, NP_001354683, NP_001354684, NP_001354685, NP_055319* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002653	Znf_A20	Domain
IPR003123	VPS9	Domain
IPR037191	VPS9_dom_sf	Homologous_superfamily
IPR041545	DUF5601	Domain
IPR045046	Vps9-like	Family

Pfam: PF01754, PF02204, PF18151

UniProt features (49 total): helix 17, modified residue 8, mutagenesis site 5, binding site 4, turn 4, region of interest 3, splice variant 2, chain 1, domain 1, zinc finger region 1, sequence conflict 1, strand 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4N3X	X-RAY DIFFRACTION	2
2C7N	X-RAY DIFFRACTION	2.1
2OT3	X-RAY DIFFRACTION	2.1
4N3Y	X-RAY DIFFRACTION	2.2
1TXU	X-RAY DIFFRACTION	2.35
2C7M	X-RAY DIFFRACTION	2.4
4N3Z	X-RAY DIFFRACTION	3.1
4Q9U	X-RAY DIFFRACTION	4.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJ41-F1	78.30	0.43

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 (4): 38; 19; 23; 35

Post-translational modifications (8): 124, 132, 151, 170, 373, 377, 390, 400

Mutagenesis-validated functional residues (5):

Position	Phenotype
58	reduces affinity for ubiquitin 3-fold.
313	strongly reduced activity.
317	strongly reduced activity.
354	strongly reduced activity.
357	strongly reduced activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8854214	TBC/RABGAPs
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 306 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_AXO_DENDRITIC_TRANSPORT, GCM_GSPT1, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_EXOCYTOSIS, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (22): negative regulation of leukocyte migration (GO:0002686), protein targeting to membrane (GO:0006612), receptor-mediated endocytosis (GO:0006898), Ras protein signal transduction (GO:0007265), protein transport (GO:0015031), endosomal transport (GO:0016197), negative regulation of interleukin-6 production (GO:0032715), negative regulation of mast cell cytokine production (GO:0032764), negative regulation of mast cell activation (GO:0033004), Kit signaling pathway (GO:0038109), mast cell degranulation (GO:0043303), negative regulation of mast cell degranulation (GO:0043305), negative regulation of Ras protein signal transduction (GO:0046580), negative regulation of receptor-mediated endocytosis (GO:0048261), negative regulation of inflammatory response (GO:0050728), regulation of Fc receptor mediated stimulatory signaling pathway (GO:0060368), mast cell migration (GO:0097531), dendritic transport (GO:0098935), negative regulation of Kit signaling pathway (GO:1900235), endocytosis (GO:0006897), vesicle-mediated transport (GO:0016192), establishment of localization in cell (GO:0051649)

GO Molecular Function (7): DNA binding (GO:0003677), guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleolus (GO:0005730), early endosome (GO:0005769), cytosol (GO:0005829), endocytic vesicle (GO:0030139), dendrite (GO:0030425), early endosome membrane (GO:0031901), recycling endosome (GO:0055037), presynaptic endosome (GO:0098830), cytoplasm (GO:0005737), endosome (GO:0005768), vesicle (GO:0031982)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Rab regulation of trafficking	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	3
vesicle-mediated transport	2
cellular anatomical structure	2
cytoplasmic vesicle	2
negative regulation of immune system process	1
regulation of leukocyte migration	1
negative regulation of cell migration	1
leukocyte migration	1
protein targeting	1
establishment of protein localization to membrane	1
endocytosis	1
small GTPase-mediated signal transduction	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
intracellular transport	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
negative regulation of cytokine production involved in immune response	1
mast cell cytokine production	1
regulation of mast cell cytokine production	1
negative regulation of leukocyte activation	1
regulation of mast cell activation	1
mast cell activation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to stem cell factor stimulus	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
negative regulation of myeloid leukocyte mediated immunity	1
negative regulation of leukocyte degranulation	1
mast cell degranulation	1
regulation of mast cell degranulation	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1

Protein interactions and networks

STRING

3076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RABGEF1	RABEP1	Q15276	999
RABGEF1	RAB5A	P20339	998
RABGEF1	EEA1	Q15075	975
RABGEF1	RAB21	Q9UL25	911
RABGEF1	RABEP2	Q9H5N1	903
RABGEF1	RAB22A	Q9UL26	880
RABGEF1	MON1A	Q86VX9	841
RABGEF1	RBSN	Q9H1K0	802
RABGEF1	CCZ1B	P86790	791
RABGEF1	RAB4A	P20338	791
RABGEF1	RABIF	P47224	761
RABGEF1	GGA1	Q9UJY5	734
RABGEF1	RAB3IP	Q96QF0	684
RABGEF1	RAB8A	P24407	674
RABGEF1	ALS2	Q96Q42	663

IntAct

131 interactions, top by confidence:

A	B	Type	Score
YWHAG	RABGEF1	psi-mi:“MI:0915”(physical association)	0.810
YWHAB	RABGEF1	psi-mi:“MI:0915”(physical association)	0.750
SLMAP	STRN	psi-mi:“MI:0914”(association)	0.710
SLMAP	STRN	psi-mi:“MI:2364”(proximity)	0.710
RABEP1	RABGEF1	psi-mi:“MI:0915”(physical association)	0.670
UBB	RABGEF1	psi-mi:“MI:0407”(direct interaction)	0.630
RABGEF1	UBB	psi-mi:“MI:0915”(physical association)	0.630
UBB	RABGEF1	psi-mi:“MI:0915”(physical association)	0.630
RABGEF1	UBB	psi-mi:“MI:0914”(association)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
EGFR	RABGEF1	psi-mi:“MI:0915”(physical association)	0.600
RABGEF1	EGFR	psi-mi:“MI:0915”(physical association)	0.600
RABGEF1	EGFR	psi-mi:“MI:0403”(colocalization)	0.600
TEAD4	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	ZC2HC1C	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	UBC	psi-mi:“MI:0915”(physical association)	0.560
THOC1	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
TXN2	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
CIPC	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	TRIM54	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	TRIM15	psi-mi:“MI:0915”(physical association)	0.560
BLOC1S6	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
ZC2HC1C	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
UBC	RABGEF1	psi-mi:“MI:0915”(physical association)	0.560
RABGEF1	THOC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (294): RABGEF1 (Affinity Capture-Western), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), RABGEF1 (Two-hybrid), TRIM54 (Two-hybrid), ZC2HC1C (Two-hybrid), CIPC (Two-hybrid), TRIM15 (Two-hybrid), UBC (Reconstituted Complex), RABGEF1 (Affinity Capture-MS), KXD1 (Two-hybrid)

ESM2 similar proteins: A0A098DRQ4, A1A4L0, A1CAN8, A1DF15, A1L1C7, A6RJQ7, A7E559, A7KAL4, B2AVN3, C8VDI2, C8VDQ4, I1RKA1, I1S4N7, O60749, O95219, P0C220, P83094, Q0WQF4, Q2TBW7, Q2U7R4, Q2UB56, Q4IR87, Q4WCV3, Q4WUE5, Q4WZF1, Q524W4, Q5AZC9, Q5R4C2, Q5R6M6, Q5R9A9, Q6NRZ4, Q6P3Q6, Q6PCS4, Q6VVX2, Q7SB54, Q7SB97, Q8J2R3, Q8K3H0, Q8VWF1, Q91VH2

Diamond homologs: A2RV61, A5D794, A8WVM4, Q10NQ3, Q14C86, Q6PAR5, Q9GYH7, Q9LT31, Q9UJ41, Q9VZ08, A2YEZ6, A2Z2J6, A3BDI8, A3C039, B5DF11, D3Z3C6, O18973, O76080, O88878, P0C282, Q0DJC7, Q3EA33, Q3SZY7, Q497H0, Q5JLA7, Q5JN07, Q5R7S6, Q5U2M7, Q69LE0, Q6DGF4, Q6FIF0, Q6H7P8, Q6NNI8, Q6Z541, Q7Y1W9, Q84PD8, Q852K5, Q852K6, Q852K8, Q86XD8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RABEP1	up-regulates	RABGEF1	binding
RABGEF1	up-regulates	RAB5A	binding
“AP-1/clathrin vescicle”	“up-regulates activity”	RABGEF1	relocalization
RABGEF1	“up-regulates activity”	RAB5A	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	61.1×	3e-09
Activation of BAD and translocation to mitochondria	6	59.3×	5e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	52.4×	1e-07
InlB-mediated entry of Listeria monocytogenes into host cell	5	49.4×	2e-06
Activation of BH3-only proteins	6	38.7×	6e-07
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	37.1×	8e-06
Negative regulation of MET activity	5	33.7×	1e-05
RHO GTPases activate PKNs	8	33.0×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	17.4×	2e-03
endocytic recycling	5	12.7×	6e-03
intracellular protein localization	7	7.0×	7e-03
protein transport	12	5.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2136 predictions. Top by Δscore:

Variant	Effect	Δscore
7:66771964:G:GT	donor_gain	1.0000
7:66772020:G:T	donor_gain	1.0000
7:66772086:GACT:G	donor_gain	1.0000
7:66775222:TGCA:T	acceptor_loss	1.0000
7:66775224:CA:C	acceptor_loss	1.0000
7:66775225:A:AC	acceptor_loss	1.0000
7:66775225:A:AG	acceptor_gain	1.0000
7:66775226:G:GA	acceptor_gain	1.0000
7:66775226:GA:G	acceptor_gain	1.0000
7:66775389:GAAGG:G	donor_gain	1.0000
7:66775391:AGGG:A	donor_loss	1.0000
7:66775392:GG:G	donor_gain	1.0000
7:66775393:GG:G	donor_gain	1.0000
7:66775394:G:GA	donor_loss	1.0000
7:66775394:G:GG	donor_gain	1.0000
7:66775395:T:A	donor_loss	1.0000
7:66783670:A:AG	acceptor_gain	1.0000
7:66783671:G:GG	acceptor_gain	1.0000
7:66783671:GCA:G	acceptor_gain	1.0000
7:66783821:G:GT	donor_gain	1.0000
7:66783826:A:T	donor_gain	1.0000
7:66783840:GG:G	donor_gain	1.0000
7:66783841:GG:G	donor_gain	1.0000
7:66783841:GGTA:G	donor_loss	1.0000
7:66783842:G:C	donor_loss	1.0000
7:66783843:T:G	donor_loss	1.0000
7:66797362:T:TA	acceptor_gain	1.0000
7:66797363:G:A	acceptor_gain	1.0000
7:66797367:A:AG	acceptor_gain	1.0000
7:66797368:T:G	acceptor_gain	1.0000

AlphaMissense

3283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:66771954:T:A	C19S	1.000
7:66771954:T:C	C19R	1.000
7:66771955:G:C	C19S	1.000
7:66772002:T:A	C35S	1.000
7:66772002:T:C	C35R	1.000
7:66772003:G:A	C35Y	1.000
7:66772003:G:C	C35S	1.000
7:66772003:G:T	C35F	1.000
7:66772004:C:G	C35W	1.000
7:66772011:T:A	C38S	1.000
7:66772011:T:C	C38R	1.000
7:66772012:G:C	C38S	1.000
7:66799333:T:A	W247R	1.000
7:66799333:T:C	W247R	1.000
7:66805275:T:C	L319P	1.000
7:66805395:T:C	L359P	1.000
7:66808901:T:C	F365L	1.000
7:66808903:C:A	F365L	1.000
7:66808903:C:G	F365L	1.000
7:66771955:G:A	C19Y	0.999
7:66771955:G:T	C19F	0.999
7:66771956:C:G	C19W	0.999
7:66771966:T:A	C23S	0.999
7:66771966:T:C	C23R	0.999
7:66771967:G:C	C23S	0.999
7:66771979:G:A	G27D	0.999
7:66772002:T:G	C35G	0.999
7:66772006:C:T	S36F	0.999
7:66772013:C:G	C38W	0.999
7:66797413:A:T	E212V	0.999

dbSNP variants (sampled 300 via entrez): RS1000009842 (7:66683246 G>A), RS1000023059 (7:66757688 T>C), RS1000026947 (7:66797719 G>A), RS1000053777 (7:66766278 T>C), RS1000059652 (7:66798110 C>G,T), RS1000092385 (7:66804390 A>C), RS1000111166 (7:66691878 A>G,T), RS1000146758 (7:66810710 G>A), RS1000152936 (7:66682875 G>C), RS1000172398 (7:66763176 T>A), RS1000181868 (7:66688766 C>T), RS1000189117 (7:66653230 G>T), RS1000211645 (7:66810849 T>TGG), RS1000212694 (7:66688270 A>G), RS1000250263 (7:66751273 C>G,T)

Disease associations

OMIM: gene MIM:609700 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000943_4	Aortic root size	4.000000e-07
GCST005667_12	Central corneal thickness	1.000000e-18
GCST005667_24	Central corneal thickness	6.000000e-08
GCST90000654_43	Central corneal thickness	5.000000e-25

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005213	central corneal thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, affects expression	3
Tobacco Smoke Pollution	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
coumarin	affects phosphorylation	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	affects phosphorylation	1
Hydralazine	affects cotreatment, increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Plant Oils	increases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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