ARFGEF1

Summary

ARFGEF1 (ARF guanine nucleotide exchange factor 1, HGNC:15772) is a protein-coding gene on chromosome 8q13.2, encoding Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (Q9Y6D6). Promotes guanine-nucleotide exchange on ARF1 and ARF3.

ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition.

Source: NCBI Gene 10565 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 764 total — 47 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• MANE Select transcript: NM_006421

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15772
Approved symbol	ARFGEF1
Name	ARF guanine nucleotide exchange factor 1
Location	8q13.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434L057, BIG1, ARFGEP1, p200
Ensembl gene	ENSG00000066777
Ensembl biotype	protein_coding
OMIM	604141
Entrez	10565

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262215, ENST00000517955, ENST00000518230, ENST00000518290, ENST00000518789, ENST00000519436, ENST00000520381, ENST00000522878, ENST00000882639, ENST00000882640, ENST00000882641, ENST00000938941

RefSeq mRNA: 15 — MANE Select: NM_006421 NM_001413184, NM_001413185, NM_001413186, NM_001413187, NM_001413188, NM_001413189, NM_001413190, NM_001413191, NM_001413192, NM_001413193, NM_001413194, NM_001413195, NM_001413196, NM_001413197, NM_006421

CCDS: CCDS6199

Canonical transcript exons

ENST00000262215 — 39 exons

Exon	Start	End
ENSE00000819569	67299209	67299355
ENSE00000928454	67291847	67292123
ENSE00000980673	67227137	67227309
ENSE00000980674	67226023	67226183
ENSE00000980675	67224903	67225033
ENSE00000980677	67218003	67218138
ENSE00000980678	67217782	67217920
ENSE00000980679	67216590	67216662
ENSE00000980680	67211483	67211615
ENSE00001033525	67296431	67296610
ENSE00001033594	67301224	67301380
ENSE00001033608	67302436	67302466
ENSE00001033609	67251299	67251450
ENSE00001090024	67277282	67277457
ENSE00001090025	67287955	67288065
ENSE00001090026	67266006	67266207
ENSE00001090028	67259815	67259926
ENSE00001090033	67275976	67276109
ENSE00001090036	67238343	67238493
ENSE00001090037	67267343	67267442
ENSE00001090038	67271702	67271936
ENSE00001090039	67240162	67240290
ENSE00001090045	67267091	67267230
ENSE00001090049	67257732	67257816
ENSE00001090051	67258085	67258290
ENSE00001361276	67343164	67343781
ENSE00001597011	67227447	67227598
ENSE00001674834	67266876	67266984
ENSE00001690304	67219431	67219560
ENSE00001693365	67253451	67253622
ENSE00001803143	67238735	67238893
ENSE00002132225	67197658	67199098
ENSE00003469371	67228224	67228264
ENSE00003472236	67203083	67203251
ENSE00003480479	67200396	67200513
ENSE00003490656	67232855	67232945
ENSE00003517318	67201467	67201605
ENSE00003569924	67227963	67228132
ENSE00003579020	67204680	67204819

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 96.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9713 / max 580.1176, expressed in 1810 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93443	13.7228	1751
93439	6.0760	1598
93447	4.5370	1597
93438	0.6587	310
93445	0.3785	171
93442	0.3618	167
93444	0.3584	159
93448	0.3290	139
93437	0.1688	59
93440	0.1423	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.72	gold quality
secondary oocyte	CL:0000655	94.45	gold quality
epithelium of nasopharynx	UBERON:0001951	94.29	gold quality
nasopharynx	UBERON:0001728	94.27	gold quality
sural nerve	UBERON:0015488	94.12	gold quality
bronchial epithelial cell	CL:0002328	93.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.67	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.65	gold quality
jejunal mucosa	UBERON:0000399	93.49	gold quality
bone marrow	UBERON:0002371	93.42	gold quality
tibia	UBERON:0000979	93.33	gold quality
bone element	UBERON:0001474	93.32	gold quality
epithelium of bronchus	UBERON:0002031	93.28	gold quality
bronchus	UBERON:0002185	93.23	gold quality
testis	UBERON:0000473	93.13	gold quality
lower esophagus mucosa	UBERON:0035834	93.12	gold quality
bone marrow cell	CL:0002092	93.03	gold quality
trabecular bone tissue	UBERON:0002483	93.02	gold quality
left testis	UBERON:0004533	92.97	gold quality
colonic mucosa	UBERON:0000317	92.95	gold quality
right testis	UBERON:0004534	92.93	gold quality
esophagus squamous epithelium	UBERON:0006920	92.72	gold quality
mucosa of transverse colon	UBERON:0004991	92.67	gold quality
nasal cavity epithelium	UBERON:0005384	92.61	gold quality
upper leg skin	UBERON:0004262	92.25	gold quality
amniotic fluid	UBERON:0000173	92.12	gold quality
tongue squamous epithelium	UBERON:0006919	92.03	gold quality
skin of leg	UBERON:0001511	91.96	gold quality
oviduct epithelium	UBERON:0004804	91.87	gold quality
skin of abdomen	UBERON:0001416	91.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

177 targeting ARFGEF1, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
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-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382

Literature-anchored findings (GeneRIF, showing 23)

• BIG1 binds to FKBP13, playing a role in vesicular trafficking (PMID:12606707)
• data are consistent with independent intracellular movements and actions of BIG1 and BIG2, and they are also evidence of the participation of BIG1 in both Golgi and nuclear functions (PMID:14973189)
• myosin IXb binds to BIG1, which regulates its Rho-GTPase activating protein activity (PMID:15644318)
• Two critical elements of BIG1 molecular structure were identified, as well as the potential function of microtubules in a novel PKA effect on BIG1 translocation. (PMID:16467138)
• Two different poliovirus proteins independently recruit different Arf GEFs (GBF1 and BIG1/2) to membranes as part of cellular pathways utilized by the virus to form its membranous replication complex. (PMID:17079330)
• results indicate a previously unrecognized role for BIG1 in the glycosylation of beta1 by Golgi enzymes, which is critical for its function in developmental and other vital cell processes (PMID:17227842)
• Phosphorylation of BIG1 and BIG2 via PKA and protein phosphatase 1gamma effects vesicular trafficking via alterations in ARF activation. (PMID:17360629)
• COPII is the only coat required for sorting and export from the endoplasmic reticulum exit sites, whereas GBF1 but not BIGs, is required for COPI recruitment, Golgi subcompartmentalization, and cargo progression to the cell surface. (PMID:18003980)
• Evidence that BIG1 and nucleolin, but not fibrillarin, can be present with p62 at the nuclear envelope confirms the presence of BIG1 and nucleolin in dynamic molecular complexes that change in composition while moving through nuclei (PMID:18292223)
• These observations indicate that BIG2 and BIG1 play redundant roles in trafficking between the trans-Golgi network and endosomes that involves the AP-1 complex. (PMID:18417613)
• Overexpression of full-length KIF21A and BIG1 and their fragments in HEK293 cells followed by reciprocal IP revealed that the C-terminal tail of KIF21A, with seven WD-40 repeats, may interact with structure in the C-terminal region of BIG1. (PMID:19020088)
• Promoter methylations of CAMK2B and ARFGEF1 are novel epigenetic markers identified in breast cancer cell lines. (PMID:21871176)
• BIG1 and KANK1 play roles in regulating cell polarity during directed migration in wound healing. (PMID:22084092)
• BIG1, through its ability to activate ADP-ribosylation factor 1, regulates cell-surface levels and function of ABCA1. (PMID:23220274)
• an early acting GEF (GBF1) activates ARFs that mediate recruitment of late acting GEFs (BIG1/2) to coordinate coating events within the pre-Golgi/Golgi/TGN continuum. (PMID:23386609)
• Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex. (PMID:23918382)
• Both phospholipase D activity and vesicular trafficking were required for effects of BIG1 and BIG2 on beta-catenin activation. Levels of PKA-phosphorylated beta-catenin S675 and beta-catenin association with PKA, BIG1, and BIG2 were also diminished after BIG1/BIG2 depletion. (PMID:27162341)
• The findings provide structural insight into how Arf1 GEFs, and hence active Arf1, achieve their correct subcellular distribution. (PMID:27373159)
• The data demonstrate a novel and unexpected function of BIG1 that regulates TNFR1 signaling by targeting TRAF2. (PMID:27834853)
• BIG1 and BIG2 knockdown significantly decreased the levels of VEGF mRNA and protein in glioblastoma U251 cells and HUVECs. Furthermore, depletion of BIG1 and BIG2 inhibited HUVEC angiogenesis by diminishing cell migration. (PMID:31199673)
• BIG1 controls macrophage pro-inflammatory responses through ARF3-mediated PI(4,5)P2 synthesis. (PMID:32415087)
• Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity. (PMID:34113008)
• The miR-133b/brefeldin A-inhibited guanine nucleotide-exchange protein 1 (ARFGEF1) axis represses proliferation, invasion, and migration in cervical cancer cells. (PMID:35048795)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	arfgef1	ENSDARG00000063474
mus_musculus	Arfgef1	ENSMUSG00000067851
rattus_norvegicus	Arfgef1	ENSRNOG00000005703
drosophila_melanogaster	siz	FBGN0026179
drosophila_melanogaster	Sec71	FBGN0028538
drosophila_melanogaster	garz	FBGN0264560
caenorhabditis_elegans		WBGENE00007703
caenorhabditis_elegans		WBGENE00008685
caenorhabditis_elegans	agef-1	WBGENE00012386

Paralogs (15): CYTH3 (ENSG00000008256), PSD (ENSG00000059915), MON2 (ENSG00000061987), CYTH4 (ENSG00000100055), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

Brefeldin A-inhibited guanine nucleotide-exchange protein 1 — Q9Y6D6 (reviewed: Q9Y6D6)

Alternative names: ADP-ribosylation factor guanine nucleotide-exchange factor 1, p200 ARF guanine nucleotide exchange factor, p200 ARF-GEP1

All UniProt accessions (5): Q9Y6D6, E5RHL7, E5RHZ1, E5RIF2, E5RJN9

UniProt curated annotations — full annotation on UniProt →

Function. Promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturation of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competitive RhoA binding. The function in the nucleus remains to be determined.

Subunit / interactions. Homodimer. Interacts with ARFGEF2/BIG2; both proteins are probably part of the same or very similar macromolecular complexes. Interacts with FKBP2. Interacts with MYO9B. Interacts with PRKAR1A and PRKAR2A. Interacts with PPP1CC. Interacts with NCL, FBL, NUP62 and U3 small nucleolar RNA. Interacts with DPY30. Interacts with PDE3A. Interacts with KANK1. Interacts with TBC1D22A and TBC1D22B. Interacts (via N-terminus) with ARL1.

Subcellular location. Cytoplasm. Perinuclear region. Golgi apparatus. trans-Golgi network membrane. Nucleus. Nucleolus. Nucleus matrix.

Tissue specificity. Expressed in placenta, lung, heart, brain, kidney and pancreas.

Post-translational modifications. Phosphorylated. In vitro phosphorylated by PKA reducing its GEF activity and dephosphorylated by phosphatase PP1.

Disease relevance. Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (DEDISB) [MIM:619964] An autosomal dominant disorder characterized by mild to moderately impaired intellectual development, language delay, motor deficits, and behavioral abnormalities including aggression, hyperactivity, and autism spectrum disorder. About half of individuals develop various types of seizures. More variable features include dysmorphic facial features, mild ocular anomalies, and non-specific findings on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by brefeldin A.

RefSeq proteins (15): NP_001400113, NP_001400114, NP_001400115, NP_001400116, NP_001400117, NP_001400118, NP_001400119, NP_001400120, NP_001400121, NP_001400122, NP_001400123, NP_001400124, NP_001400125, NP_001400126, NP_006412* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000904	Sec7_dom	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR015403	Mon2/Sec7/BIG1-like_HDS	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR023394	Sec7_C_sf	Homologous_superfamily
IPR032629	DCB_dom	Domain
IPR032691	Mon2/Sec7/BIG1-like_HUS	Domain
IPR035999	Sec7_dom_sf	Homologous_superfamily
IPR046455	Sec7/BIG1-like_C	Domain

Pfam: PF01369, PF09324, PF12783, PF16213, PF20252

UniProt features (65 total): helix 22, modified residue 9, mutagenesis site 8, region of interest 7, sequence variant 7, sequence conflict 4, compositionally biased region 3, strand 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3LTL	X-RAY DIFFRACTION	2.2
5EE5	X-RAY DIFFRACTION	2.28
5J5C	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6D6-F1	76.23	0.42

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 (9): 52, 286, 289, 290, 397, 410, 1079, 1566, 1569

Mutagenesis-validated functional residues (8):

Position	Phenotype
105	loss of interaction with arl1.
109	lloss of interaction with arl1.
156	loss of interaction with arl1.
200	loss of interaction with arl1.
221	no effect on self-association.
712–714	inhibits nuclear localization.
883	abolishes camp-induced nuclear localization.
883	no effect on camp-induced nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 305 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, RRAGTTGT_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_WOUND_HEALING, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, MORF_HDAC2

GO Biological Process (13): exocytosis (GO:0006887), Golgi organization (GO:0007030), glycoprotein biosynthetic process (GO:0009101), endomembrane system organization (GO:0010256), protein transport (GO:0015031), negative regulation of actin filament polymerization (GO:0030837), neuron projection development (GO:0031175), regulation of ARF protein signal transduction (GO:0032012), negative regulation of GTPase activity (GO:0034260), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of wound healing (GO:0090303), regulation of establishment of cell polarity (GO:2000114), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), myosin binding (GO:0017022), protein kinase A regulatory subunit binding (GO:0034237), protein binding (GO:0005515)

GO Cellular Component (12): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), nucleolus (GO:0005730), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), nuclear matrix (GO:0016363), small nuclear ribonucleoprotein complex (GO:0030532), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
nuclear lumen	3
cytoplasm	3
intracellular membrane-bounded organelle	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
organelle organization	1
endomembrane system organization	1
macromolecule biosynthetic process	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
cellular component organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
actin filament polymerization	1
regulation of actin filament polymerization	1
negative regulation of protein polymerization	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
neuron development	1
plasma membrane bounded cell projection organization	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTPase activity	1
regulation of GTPase activity	1
negative regulation of biological process	1
negative regulation of hydrolase activity	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
establishment of cell polarity	1
regulation of establishment or maintenance of cell polarity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1

Protein interactions and networks

STRING

2074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARFGEF1	MYO9B	Q13459	857
ARFGEF1	NUP62	P37198	650
ARFGEF1	NUCLEOLIN	P19338	623
ARFGEF1	RABIF	P47224	596
ARFGEF1	FBL	P22087	550
ARFGEF1	MYO5A	Q9Y4I1	540
ARFGEF1	ARF6	P26438	539
ARFGEF1	PPP1CC	P36873	527
ARFGEF1	MYBL1	P10243	512
ARFGEF1	ARF1	P10947	505
ARFGEF1	MYBL2	P10244	495
ARFGEF1	MYO6	Q9UM54	491
ARFGEF1	RHOA	P06749	488
ARFGEF1	TMEM208	Q9BTX3	468
ARFGEF1	LYN	P07948	465

IntAct

165 interactions, top by confidence:

A	B	Type	Score
ARFGEF1	ARFGEF2	psi-mi:“MI:0915”(physical association)	0.840
ARFGEF2	ARFGEF1	psi-mi:“MI:0403”(colocalization)	0.840
ARFGEF2	ARFGEF1	psi-mi:“MI:0915”(physical association)	0.840
MYCBP	ARFGEF1	psi-mi:“MI:0915”(physical association)	0.790
ARFGEF1	MYCBP	psi-mi:“MI:0915”(physical association)	0.790
ARFGEF1	MYCBP	psi-mi:“MI:0403”(colocalization)	0.790
KANK1	KIF21A	psi-mi:“MI:0914”(association)	0.750
KIF21A	KANK1	psi-mi:“MI:0914”(association)	0.750
ARFGEF1	KIF21A	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
KIF21A	ARFGEF1	psi-mi:“MI:0915”(physical association)	0.710
ARFGEF1	KIF21A	psi-mi:“MI:0403”(colocalization)	0.710
KIF21A	ARFGEF1	psi-mi:“MI:0403”(colocalization)	0.710
ARFGEF1	KANK1	psi-mi:“MI:0914”(association)	0.630
ARFGEF1	KANK1	psi-mi:“MI:0407”(direct interaction)	0.630
ARFGEF1	KANK1	psi-mi:“MI:0915”(physical association)	0.630
ARFGEF1	PDE3A	psi-mi:“MI:0914”(association)	0.580
ARFGEF1	PDE3A	psi-mi:“MI:0915”(physical association)	0.580
MYO9B	ARFGEF1	psi-mi:“MI:0407”(direct interaction)	0.560
ARFGEF1	MYO9B	psi-mi:“MI:0407”(direct interaction)	0.560
MYCBP	AKAP8	psi-mi:“MI:0914”(association)	0.550
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530

BioGRID (211): ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Two-hybrid), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5P556, A0A3Q1LSX9, A2A5R2, A2APV2, B0DOB5, B2RQE8, D3ZYR1, D4A631, F1LVW7, F1M775, F4IUX6, G3X9K3, O08808, O46382, O60308, O60610, O75674, O95466, Q07139, Q0IHV1, Q0JRZ9, Q3UQN2, Q4S6U8, Q5MIZ7, Q5R807, Q5SP90, Q6DFT3, Q6IN85, Q6INN7, Q6NTV6, Q6NXC0, Q6P2K6, Q6ZPF4, Q7TSU1, Q7ZX60, Q801Q7, Q80U19, Q86T65, Q8BPM0, Q8IVF7

Diamond homologs: A0A0G2JUG7, A2A5R2, A5PKW4, D4A631, E1JIT7, F1MUS9, F4IXW2, F4JN05, F4JSZ5, F4K2K3, G3X9K3, G5EET6, O08967, O13690, O13817, O43739, O46382, P11075, P34512, P39993, P47102, P63034, P63035, P97694, P97696, Q10491, Q15438, Q2KI41, Q2PFD7, Q3TES0, Q42510, Q54KA7, Q5DTT2, Q5DU25, Q5E9G6, Q5JU85, Q6DFZ1, Q6DN90, Q6P1I6, Q76M68

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PRKACA	“up-regulates activity”	ARFGEF1	phosphorylation
ARFGEF1	“up-regulates activity”	ARF1	“guanine nucleotide exchange factor”
ARFGEF1	“up-regulates activity”	ARF3	“guanine nucleotide exchange factor”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	35
Uncertain significance	459
Likely benign	139
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100669	NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter)	Pathogenic
1069030	NM_001382391.1(CSPP1):c.2980C>T (p.Arg994Ter)	Pathogenic
1072911	NM_001382391.1(CSPP1):c.3406_3407insTATA (p.Arg1136delinsIleTer)	Pathogenic
1322167	NM_001382391.1(CSPP1):c.3142C>T (p.Arg1048Ter)	Pathogenic
1445486	NM_001382391.1(CSPP1):c.3405_3406del (p.Arg1136fs)	Pathogenic
1455984	NM_001382391.1(CSPP1):c.3368_3371del (p.Leu1122_Ser1123insTer)	Pathogenic
148965	GRCh38/hg38 8q13.1-21.13(chr8:66633845-80100089)x3	Pathogenic
1697327	NM_006421.5(ARFGEF1):c.4365C>A (p.Cys1455Ter)	Pathogenic
1723033	NM_006421.5(ARFGEF1):c.4244_4245del (p.Tyr1415fs)	Pathogenic
1933382	NM_001382391.1(CSPP1):c.3266del (p.Pro1089fs)	Pathogenic
217645	NM_001382391.1(CSPP1):c.3220+1G>A	Pathogenic
2426888	NC_000008.10:g.(?67976634)(68658364_?)del	Pathogenic
2506326	NC_000008.10:g.(?68109883)(68255913_?)del	Pathogenic
2591624	NM_006421.5(ARFGEF1):c.5164C>T (p.Gln1722Ter)	Pathogenic
2616872	NM_006421.5(ARFGEF1):c.3814C>T (p.Arg1272Ter)	Pathogenic
2627922	NM_006421.5(ARFGEF1):c.4627C>T (p.Arg1543Ter)	Pathogenic
2663110	NM_006421.5(ARFGEF1):c.1922-2A>G	Pathogenic
2664612	NM_006421.5(ARFGEF1):c.2203C>T (p.Gln735Ter)	Pathogenic
2664990	NM_006421.5(ARFGEF1):c.996_1005del (p.Val333fs)	Pathogenic
2673150	NM_006421.5(ARFGEF1):c.4831_4832del (p.Gln1611fs)	Pathogenic
3027226	NM_006421.5(ARFGEF1):c.3289+1G>A	Pathogenic
3075703	NM_006421.5(ARFGEF1):c.2925_2926del (p.Cys976fs)	Pathogenic
3255194	NM_006421.5(ARFGEF1):c.3799C>T (p.Gln1267Ter)	Pathogenic
3370921	NM_006421.5(ARFGEF1):c.491_492del (p.Ile164fs)	Pathogenic
3375639	NM_006421.5(ARFGEF1):c.2316_2317del (p.Ser773fs)	Pathogenic
3377160	NM_006421.5(ARFGEF1):c.1240_1241del (p.Lys414fs)	Pathogenic
3420545	NM_006421.5(ARFGEF1):c.1420_1424del (p.Asn474fs)	Pathogenic
3573029	NM_006421.5(ARFGEF1):c.3539T>G (p.Ile1180Arg)	Pathogenic
3717557	NM_001382391.1(CSPP1):c.3067C>T (p.Gln1023Ter)	Pathogenic
3903263	NM_006421.5(ARFGEF1):c.3220C>T (p.Arg1074Ter)	Pathogenic

SpliceAI

6949 predictions. Top by Δscore:

Variant	Effect	Δscore
8:67175289:A:AG	acceptor_gain	1.0000
8:67175290:T:G	acceptor_gain	1.0000
8:67175291:A:AG	acceptor_gain	1.0000
8:67175292:CCAGA:C	acceptor_loss	1.0000
8:67175294:A:AG	acceptor_gain	1.0000
8:67175295:G:GT	acceptor_gain	1.0000
8:67175295:GA:G	acceptor_gain	1.0000
8:67175424:G:GT	donor_gain	1.0000
8:67175425:A:T	donor_gain	1.0000
8:67175435:AG:A	donor_gain	1.0000
8:67175436:GG:G	donor_gain	1.0000
8:67175436:GGTA:G	donor_loss	1.0000
8:67175437:G:GG	donor_gain	1.0000
8:67177669:A:AG	acceptor_gain	1.0000
8:67177669:ATT:A	acceptor_gain	1.0000
8:67177670:T:G	acceptor_gain	1.0000
8:67177671:T:A	acceptor_gain	1.0000
8:67177678:A:AG	acceptor_gain	1.0000
8:67177679:G:GC	acceptor_gain	1.0000
8:67177679:GT:G	acceptor_gain	1.0000
8:67177679:GTT:G	acceptor_gain	1.0000
8:67200510:GACA:G	acceptor_gain	1.0000
8:67200512:CA:C	acceptor_gain	1.0000
8:67200513:ACTG:A	acceptor_loss	1.0000
8:67200514:C:CC	acceptor_gain	1.0000
8:67200514:CTGCA:C	acceptor_loss	1.0000
8:67201464:TACT:T	donor_loss	1.0000
8:67201465:A:AC	donor_gain	1.0000
8:67201466:C:CA	donor_gain	1.0000
8:67201466:CT:C	donor_gain	1.0000

AlphaMissense

12263 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:67200452:A:G	W1777R	1.000
8:67200452:A:T	W1777R	1.000
8:67201578:A:G	L1719P	1.000
8:67201584:G:T	P1717H	1.000
8:67203094:A:G	L1706P	1.000
8:67203102:C:A	R1703S	1.000
8:67203102:C:G	R1703S	1.000
8:67203103:C:A	R1703M	1.000
8:67203120:A:C	N1697K	1.000
8:67203120:A:T	N1697K	1.000
8:67203123:A:C	F1696L	1.000
8:67203123:A:T	F1696L	1.000
8:67203125:A:G	F1696L	1.000
8:67204759:A:G	L1627P	1.000
8:67217896:C:T	G1500D	1.000
8:67218105:C:G	A1458P	1.000
8:67218127:C:A	W1450C	1.000
8:67218127:C:G	W1450C	1.000
8:67218129:A:G	W1450R	1.000
8:67218129:A:T	W1450R	1.000
8:67219464:A:C	F1435L	1.000
8:67219464:A:T	F1435L	1.000
8:67219466:A:G	F1435L	1.000
8:67219499:A:G	W1424R	1.000
8:67219499:A:T	W1424R	1.000
8:67219559:C:G	G1404R	1.000
8:67224908:T:A	R1401S	1.000
8:67224908:T:G	R1401S	1.000
8:67224909:C:A	R1401I	1.000
8:67224909:C:G	R1401T	1.000

dbSNP variants (sampled 300 via entrez): RS1000002304 (8:67328389 C>A,T), RS1000016633 (8:67285953 C>T), RS1000050220 (8:67196242 A>G), RS1000074556 (8:67199947 C>G), RS1000145335 (8:67180380 G>A), RS1000151611 (8:67240989 T>C), RS1000177891 (8:67279032 G>A), RS1000185973 (8:67214200 T>C), RS1000193452 (8:67258991 C>T), RS1000198589 (8:67237985 C>A), RS1000202654 (8:67269383 G>A,T), RS1000208793 (8:67281746 A>C,G,T), RS1000266245 (8:67258851 AC>A), RS1000269811 (8:67278934 C>T), RS1000298740 (8:67308930 A>C)

Disease associations

OMIM: gene MIM:604141 | disease phenotypes: MIM:615636, MIM:619964, MIM:619475

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental delay, impaired speech, and behavioral abnormalities, with or without seizures	Definitive	Autosomal dominant
schizophrenia	Limited	Unknown

Mondo (7): Joubert syndrome 21 (MONDO:0014288), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (MONDO:0859263), developmental delay, impaired speech, and behavioral abnormalities (MONDO:0859178), inherited retinal dystrophy (MONDO:0019118), schizophrenia (MONDO:0005090)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

12 total (13 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0002069	Bilateral tonic-clonic seizure
HP:0002521	Hypsarrhythmia
HP:0003593	Infantile onset
HP:0008936	Axial hypotonia
HP:0010819	Atonic seizure
HP:0010841	Multifocal epileptiform discharges
HP:0012469	Infantile spasms
HP:0032792	Tonic seizure
HP:0032794	Myoclonic seizure
HP:0000556	Retinal dystrophy

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002543_4	Hearing function	3.000000e-07
GCST006416_2	Chronic central serous retinopathy	1.000000e-07
GCST008156_54	Hip circumference adjusted for BMI	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009363	chronic central serous retinopathy
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067179 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.29	Kd	515.7	nM	CHEMBL5653589
6.29	ED50	515.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147883: Binding affinity to human ARFGEF1 incubated for 45 mins by Kinobead based pull down assay	kd	0.5157	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases reaction, increases abundance, decreases expression	3
Nickel	affects expression, increases expression, decreases reaction	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	increases expression	1
trichostatin A	affects expression, decreases reaction	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	decreases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
K 7174	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650925	Binding	Binding affinity to human ARFGEF1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety