ARF4

Summary

ARF4 (ARF GTPase 4, HGNC:655) is a protein-coding gene on chromosome 3p14.3, encoding ADP-ribosylation factor 4 (P18085). GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. It is a selective cancer dependency (DepMap: 61.3% of cell lines).

This gene is a member of the human ARF gene family whose members encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 5 ARF proteins and 11 ARF-like proteins and constitute one family of the RAS superfamily. The ARF proteins are categorized as class I, class II and class III; this gene is a class II member. The members of each class share a common gene organization. The ARF4 gene spans approximately 12kb and contains six exons and five introns. This gene is the most divergent member of the human ARFs. Conflicting map positions at 3p14 or 3p21 have been reported for this gene.

Source: NCBI Gene 378 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 13 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 61.3% of screened cell lines
• MANE Select transcript: NM_001660

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:655
Approved symbol	ARF4
Name	ARF GTPase 4
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000168374
Ensembl biotype	protein_coding
OMIM	601177
Entrez	378

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000303436, ENST00000463880, ENST00000483848, ENST00000486310, ENST00000488156, ENST00000489843, ENST00000493378, ENST00000495354, ENST00000496292, ENST00000896579, ENST00000896580, ENST00000922177, ENST00000948644

RefSeq mRNA: 1 — MANE Select: NM_001660 NM_001660

CCDS: CCDS2884

Canonical transcript exons

ENST00000303436 — 6 exons

Exon	Start	End
ENSE00001122583	57571363	57572298
ENSE00001818007	57597074	57597344
ENSE00002390260	57583898	57584007
ENSE00003473036	57577316	57577387
ENSE00003695608	57575548	57575673
ENSE00003697925	57584384	57584464

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 337.6242 / max 6071.7840, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42659	224.8231	1827
42660	96.6967	1823
42661	16.1044	1794

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.78	gold quality
parietal pleura	UBERON:0002400	99.69	gold quality
visceral pleura	UBERON:0002401	99.68	gold quality
pleura	UBERON:0000977	99.66	gold quality
germinal epithelium of ovary	UBERON:0001304	99.65	gold quality
corpus epididymis	UBERON:0004359	99.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.50	gold quality
esophagus squamous epithelium	UBERON:0006920	99.44	gold quality
epithelial cell of pancreas	CL:0000083	99.38	gold quality
parotid gland	UBERON:0001831	99.36	gold quality
colonic mucosa	UBERON:0000317	99.34	gold quality
epithelium of nasopharynx	UBERON:0001951	99.30	gold quality
nasopharynx	UBERON:0001728	99.28	gold quality
stromal cell of endometrium	CL:0002255	99.23	gold quality
endometrium	UBERON:0001295	99.23	gold quality
gingival epithelium	UBERON:0001949	99.23	gold quality
cauda epididymis	UBERON:0004360	99.23	gold quality
seminal vesicle	UBERON:0000998	99.22	gold quality
type B pancreatic cell	CL:0000169	99.21	gold quality
choroid plexus epithelium	UBERON:0003911	99.19	gold quality
caput epididymis	UBERON:0004358	99.19	gold quality
trachea	UBERON:0003126	99.16	gold quality
pylorus	UBERON:0001166	99.13	gold quality
palpebral conjunctiva	UBERON:0001812	99.13	gold quality
gingiva	UBERON:0001828	99.12	gold quality
smooth muscle tissue	UBERON:0001135	99.10	gold quality
jejunal mucosa	UBERON:0000399	99.09	gold quality
epithelium of esophagus	UBERON:0001976	99.09	gold quality
islet of Langerhans	UBERON:0000006	99.08	gold quality
placenta	UBERON:0001987	99.06	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	1987.98
E-MTAB-10485	yes	1190.05
E-MTAB-6701	yes	51.86
E-MTAB-8410	yes	33.66
E-GEOD-134144	yes	30.88
E-CURD-112	yes	16.11
E-HCAD-1	yes	7.95
E-MTAB-10042	yes	7.95
E-MTAB-7052	no	1275.97
E-MTAB-6108	no	575.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB3, MYC

miRNA regulators (miRDB)

118 targeting ARF4, 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-4283	100.00	66.42	2097
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-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 61.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• ARF4 is a critical molecule that directly regulates cellular phospholipase D2 activity and this ARF4-mediated PLD2 activation stimulates AP-1-dependent transcription in the EGF-induced cellular response (PMID:12446727)
• ARF4L occurred on the plasma membrane after binding to GTP and into endosomes while binding to GDP; the inactive form of ARF4L causes localization of transferrin receptors to the endosomes while the active form causes transport to the plasma membrane. (PMID:15049518)
• ARF4 participates in the regulation of glioblastoma apoptosis through the inhibition of stress-mediated apoptotic signals (PMID:19041174)
• Arf4 regulates PLA2G6-A activity together with Arf1; and gene silencing of Arf4 was shown to alter cytosolic coat protein I subunit recruitment to the early secretory pathway. (PMID:20881058)
• sLZIP-regulated ARF4 expression in response to phorbol 12-myristate 13-acetate is involved in breast cancer cell migration. (PMID:22004728)
• a crucial role for class II Arf proteins (Arf4 and Arf5) in the dengue flavivirus life cycle (PMID:22105072)
• The lipid droplets deposition and the cellular triacylglycerol content are significantly increased by siRNA-mediated depletion of Arf4. (PMID:22185782)
• ARF1+ARF4 are required for integrity of recycling endosomes but are involved in distinct transport pathways: the pair regulates retrograde transport from endosomes to the TGN. (PMID:23783033)
• A CREB3-ARF4 signalling cascade may be part of a Golgi stress response set in motion by stimuli compromising Golgi capacity. (PMID:24185178)
• found ADP-ribosylation factor (ARF) 4 is one of the putative target genes of Mir-221, and the direct binding relationship was further confirmed by dual-luciferase reporter assay. (PMID:28057486)
• Data suggest that, when compared to intestinal epithelial cells (IECs) from germ-free mice, IECs from mice with commensal bacteria exhibit increased expression of microRNA-21-5p; up-regulation of expression of microRNA-21-5p appears to increase IEC permeability and up-regulates ADP ribosylation factor 4 (Arf4/ARF4) in mouse and human cells. (PMID:28760826)
• In summary, the authors show here that hepatitis C virus infection is associated with an upregulation of ARF4, which promotes hepatitis C virus replication. Upon hepatitis C virus infection, CREB3 was redistributed to nucleus and activated ARF4 transcription. (PMID:28840565)
• The ins and outs of the Arf4-based ciliary membrane-targeting complex. (PMID:31068062)
• Study identified two novel sodium iodide symporter (NIS) interactors, valosin-containing protein (VCP) and ADP-ribosylation factor 4 (ARF4), with critical roles in modulating NIS function as well as correlating markedly with clinical outcome in papillary thyroid cancer. ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP governed NIS proteolysis. (PMID:31672844)
• Class II Arfs require a brefeldin-A-sensitive factor for Golgi association. (PMID:32828303)
• microRNA196a3p inhibits cell proliferation and promotes cell apoptosis by targeting ADP ribosylation factor 4 in diffuse large Bcell lymphoma. (PMID:33416178)
• Quantitative Proteomics Reveals Association of Neuron Projection Development Genes ARF4, KIF5B, and RAB8A With Hirschsprung Disease. (PMID:33561610)
• Cholesterol 25-Hydroxylase Protects Against Diabetic Kidney Disease by Regulating ADP Ribosylation Factor 4. (PMID:38816950)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Arf4	ENSMUSG00000021877
rattus_norvegicus	Arf4	ENSRNOG00000012623

Paralogs (30): ARF5 (ENSG00000004059), SAR1A (ENSG00000079332), ARFRP1 (ENSG00000101246), TRIM23 (ENSG00000113595), ARL6 (ENSG00000113966), ARL1 (ENSG00000120805), ARL4A (ENSG00000122644), ARL8B (ENSG00000134108), ARF3 (ENSG00000134287), ARL3 (ENSG00000138175), ARL5C (ENSG00000141748), ARF1 (ENSG00000143761), ARL8A (ENSG00000143862), ARL11 (ENSG00000152213), SAR1B (ENSG00000152700), ARL5A (ENSG00000162980), ARF6 (ENSG00000165527), ARL5B (ENSG00000165997), ARL13B (ENSG00000169379), ARL13A (ENSG00000174225), ARL10 (ENSG00000175414), ARL4D (ENSG00000175906), ARL14 (ENSG00000179674), ARL15 (ENSG00000185305), ARL17A (ENSG00000185829), ARL4C (ENSG00000188042), ARL9 (ENSG00000196503), ARL2 (ENSG00000213465), ARL16 (ENSG00000214087), ARL17B (ENSG00000228696)

Protein

Protein identifiers

ADP-ribosylation factor 4 — P18085 (reviewed: P18085)

All UniProt accessions (6): C9J6P1, C9JAK5, C9JPM4, P18085, F8WDB3, U3KQF2

UniProt curated annotations — full annotation on UniProt →

Function. GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking; may modulate vesicle budding and uncoating within the Golgi apparatus. Part of the ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which direct preciliary vesicle trafficking to mother centriole and ciliogenesis initiation.

Subunit / interactions. Forms a complex containing RAB11A, ASAP1, RAB3IP, RAP11FIP3 and ARF4; the complex promotes preciliary trafficking; the complex binds to RHO in photoreceptor cells and promotes RHO ciliary transport.

Subcellular location. Golgi apparatus. Membrane.

Similarity. Belongs to the small GTPase superfamily. Arf family.

RefSeq proteins (1): NP_001651* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005225	Small_GTP-bd	Domain
IPR006689	Small_GTPase_ARF/SAR	Family
IPR024156	Small_GTPase_ARF	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR045872	Arf1-5-like	Family

Pfam: PF00025

UniProt features (28 total): helix 10, strand 9, binding site 3, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1Z6X	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18085-F1	83.89	0.53

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 (3): 24–31; 67–71; 126–129

Post-translational modifications (2): 147, 2

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-5620916	VxPx cargo-targeting to cilium
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-6811442	Intra-Golgi and retrograde Golgi-to-ER traffic
R-HSA-8856688	Golgi-to-ER retrograde transport
R-HSA-948021	Transport to the Golgi and subsequent modification

MSigDB gene sets: 355 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_DENDRITE_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_DENDRITIC_SPINE_DEVELOPMENT, DITTMER_PTHLH_TARGETS_UP, HSIAO_HOUSEKEEPING_GENES, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_RESPONSE_TO_AXON_INJURY, GOCC_RUFFLE

GO Biological Process (20): intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), epidermal growth factor receptor signaling pathway (GO:0007173), learning (GO:0007612), vesicle-mediated transport (GO:0016192), cell migration (GO:0016477), negative regulation of apoptotic process (GO:0043066), apical protein localization (GO:0045176), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), positive regulation of transcription by RNA polymerase II (GO:0045944), response to axon injury (GO:0048678), cilium assembly (GO:0060271), dendritic spine development (GO:0060996), protein localization to cilium (GO:0061512), regulation of postsynapse organization (GO:0099175), regulation of cilium assembly (GO:1902017), regulation of reactive oxygen species metabolic process (GO:2000377), protein transport (GO:0015031), regulation of synapse organization (GO:0050807)

GO Molecular Function (8): GTPase activity (GO:0003924), guanyl-nucleotide exchange factor activity (GO:0005085), epidermal growth factor receptor binding (GO:0005154), GTP binding (GO:0005525), NAD+-protein-arginine ADP-ribosyltransferase activity (GO:0106274), phospholipase D activator activity (GO:1990583), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), ruffle membrane (GO:0032587), dendritic spine (GO:0043197), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Membrane Trafficking	2
Cargo trafficking to the periciliary membrane	1
ER to Golgi Anterograde Transport	1
Golgi-to-ER retrograde transport	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1
Metabolism of proteins	1
Intra-Golgi and retrograde Golgi-to-ER traffic	1
Asparagine N-linked glycosylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	3
cytoplasm	3
cellular anatomical structure	3
intracellular transport	2
Golgi vesicle transport	2
transport	2
protein transport	1
intercellular transport	1
ERBB signaling pathway	1
learning or memory	1
cellular process	1
cell motility	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
establishment or maintenance of apical/basal cell polarity	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to wounding	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
dendrite development	1
anatomical structure development	1
protein localization to organelle	1
regulation of synapse organization	1
postsynapse organization	1
cilium assembly	1
regulation of plasma membrane bounded cell projection assembly	1
regulation of organelle assembly	1
regulation of metabolic process	1
reactive oxygen species metabolic process	1
establishment of protein localization	1
regulation of synapse structure or activity	1

Protein interactions and networks

STRING

3339 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARF4	ASAP1	Q9ULH1	948
ARF4	IKBKG	Q9Y6K9	933
ARF4	RAB11A	P24410	834
ARF4	CDKN2A	P42771	789
ARF4	RHO	P08100	754
ARF4	RAB11FIP3	O75154	631
ARF4	RAB6A	P20340	628
ARF4	RAB3IP	Q96QF0	591
ARF4	CYTH1	Q15438	586
ARF4	PKD1	P98161	582
ARF4	PKD2	Q13563	579
ARF4	RASA1	P20936	577
ARF4	RAB8A	P24407	564
ARF4	NCK2	O43639	554
ARF4	COPB1	P53618	546

IntAct

154 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RAB3IP	RAB11FIP3	psi-mi:“MI:0914”(association)	0.660
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
ARF4	SDCBP2	psi-mi:“MI:0915”(physical association)	0.560
SDCBP2	ARF4	psi-mi:“MI:0915”(physical association)	0.560
ARF4	COPS3	psi-mi:“MI:0915”(physical association)	0.560
RCHY1	ARF4	psi-mi:“MI:0915”(physical association)	0.540
RCHY1	ARF4	psi-mi:“MI:0403”(colocalization)	0.540
ARF5	ARF4	psi-mi:“MI:0914”(association)	0.530
RAB11FIP3	ARF4	psi-mi:“MI:0914”(association)	0.520
RAB11FIP3	ARF4	psi-mi:“MI:0407”(direct interaction)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	MYL12B	psi-mi:“MI:0914”(association)	0.460
RAB11A	LANCL1	psi-mi:“MI:2364”(proximity)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:2364”(proximity)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
Cdk1		psi-mi:“MI:0915”(physical association)	0.400

BioGRID (383): SDCBP2 (Two-hybrid), ARF4 (Affinity Capture-RNA), ACADM (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation), ARF4 (Co-fractionation)

ESM2 similar proteins: A8ISN6, B5FYQ0, O00909, O45379, O48649, O48920, P0CM16, P0CM17, P0DH91, P18085, P25160, P36397, P36405, P37996, P38116, P40616, P40940, P49076, P49702, P51644, P51821, P56559, P61208, P61211, P61212, P61750, P61751, P84081, P84082, P84083, P84084, P84085, Q06396, Q19705, Q1MTE5, Q20758, Q2TBW6, Q2YDM1, Q3SZF2, Q52NJ4

Diamond homologs: A1CRG9, A1D4D1, A3LTA2, A5DR82, A5E5G3, A8ISN6, O04266, O04267, O04834, O45379, O48649, O48920, P0C583, P0C950, P0C951, P0CM16, P0CM17, P0CR30, P0CR31, P0CT16, P0CT17, P0DH91, P11076, P18085, P19146, P20606, P22274, P34727, P36397, P36536, P36579, P38116, P40940, P40945, P40994, P49702, P51643, P51821, P51823, P51824

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARF4	up-regulates	Vesicle_transport

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 176 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
Tie2 Signaling	5	24.4×	1e-04
Downstream signal transduction	6	18.6×	1e-04
Constitutive Signaling by Aberrant PI3K in Cancer	10	10.3×	2e-05
Signaling by SCF-KIT	5	10.1×	3e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	8	10.0×	1e-04
Regulation of RAS by GAPs	6	9.4×	1e-03
COPI-dependent Golgi-to-ER retrograde traffic	9	8.1×	1e-04
COPI-mediated anterograde transport	9	8.0×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	8	22.5×	9e-07
positive regulation of MAP kinase activity	5	21.6×	7e-04
cell surface receptor protein tyrosine kinase signaling pathway	15	17.4×	1e-11
vascular endothelial growth factor receptor signaling pathway	5	16.1×	2e-03
protein autophosphorylation	12	11.6×	3e-07
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	5	11.2×	7e-03
neuron apoptotic process	7	8.6×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	14	7.3×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

711 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57572294:TACCA:T	acceptor_gain	1.0000
3:57572295:ACCA:A	acceptor_gain	1.0000
3:57572296:CCA:C	acceptor_gain	1.0000
3:57572296:CCAC:C	acceptor_gain	1.0000
3:57572297:CA:C	acceptor_gain	1.0000
3:57572297:CAC:C	acceptor_gain	1.0000
3:57572298:ACTG:A	acceptor_loss	1.0000
3:57572299:C:CC	acceptor_gain	1.0000
3:57572301:G:C	acceptor_gain	1.0000
3:57575541:TACTT:T	donor_loss	1.0000
3:57575542:ACTTA:A	donor_loss	1.0000
3:57575543:CTTA:C	donor_gain	1.0000
3:57575544:TTAC:T	donor_loss	1.0000
3:57575545:TACTG:T	donor_loss	1.0000
3:57575546:A:AC	donor_gain	1.0000
3:57575546:AC:A	donor_loss	1.0000
3:57575547:C:CT	donor_gain	1.0000
3:57575547:CT:C	donor_gain	1.0000
3:57575547:CTG:C	donor_gain	1.0000
3:57575547:CTGT:C	donor_gain	1.0000
3:57575547:CTGTT:C	donor_gain	1.0000
3:57575669:AGAAG:A	acceptor_gain	1.0000
3:57575670:GAAG:G	acceptor_gain	1.0000
3:57575671:AAG:A	acceptor_gain	1.0000
3:57575672:AG:A	acceptor_gain	1.0000
3:57575674:C:CC	acceptor_gain	1.0000
3:57577312:TTAC:T	donor_loss	1.0000
3:57577313:TAC:T	donor_loss	1.0000
3:57577314:A:AC	donor_gain	1.0000
3:57577314:A:C	donor_loss	1.0000

AlphaMissense

1176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57575624:T:A	K127I	1.000
3:57575623:T:A	K127N	0.999
3:57575623:T:G	K127N	0.999
3:57583960:A:G	W66R	0.999
3:57583960:A:T	W66R	0.999
3:57584003:A:C	F51L	0.999
3:57584003:A:T	F51L	0.999
3:57584005:A:G	F51L	0.999
3:57584440:G:A	T31I	0.999
3:57584444:T:G	K30Q	0.999
3:57584446:C:T	G29D	0.999
3:57575625:T:C	K127E	0.998
3:57583956:T:G	D67A	0.998
3:57583957:C:G	D67H	0.998
3:57584442:C:A	K30N	0.998
3:57584442:C:G	K30N	0.998
3:57584443:T:A	K30M	0.998
3:57584447:C:G	G29R	0.998
3:57584462:C:G	G24R	0.998
3:57584462:C:T	G24R	0.998
3:57572250:C:G	G169R	0.997
3:57572250:C:T	G169R	0.997
3:57575624:T:G	K127T	0.997
3:57583956:T:A	D67V	0.997
3:57583956:T:C	D67G	0.997
3:57584446:C:A	G29V	0.997
3:57584447:C:A	G29C	0.997
3:57584461:C:T	G24E	0.997
3:57572237:A:G	L173P	0.996
3:57575626:G:C	N126K	0.996

dbSNP variants (sampled 300 via entrez): RS1000012709 (3:57590290 G>A,C), RS1000042127 (3:57578636 C>T), RS1000101374 (3:57572123 G>A,T), RS1000132113 (3:57591927 G>T), RS1000178729 (3:57596438 C>T), RS1000303415 (3:57586800 G>A), RS1000642980 (3:57577025 T>C,G), RS1000654271 (3:57587313 C>A,T), RS1000681614 (3:57593955 T>C), RS1000764267 (3:57583450 G>A), RS1000816920 (3:57583799 T>C,G), RS1001195366 (3:57570889 A>G), RS1001299668 (3:57577616 C>G), RS1001331697 (3:57574284 A>G), RS1001626791 (3:57571312 A>G)

Disease associations

OMIM: gene MIM:601177 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066949 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.63	Kd	23.46	nM	CHEMBL5653589
7.63	ED50	23.46	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2147881: Binding affinity to human ARF4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0235	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	increases expression, affects expression	2
sodium arsenite	increases expression	2
ochratoxin A	affects binding, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Rotenone	decreases expression, increases expression	2
Dronabinol	decreases expression	2
Particulate Matter	increases abundance, decreases expression	2
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
beta-lapachone	increases expression	1
bleomycetin	decreases expression	1
indirubin	decreases expression	1
ochratoxin B	affects binding	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	affects expression	1
K 7174	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Glyphosate	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diuron	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
CHEMBL5650923	Binding	Binding affinity to human ARF4 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

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SD29	HAP1 ARF4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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