ARFGEF2

Summary

ARFGEF2 (ARF guanine nucleotide exchange factor 2, HGNC:15853) is a protein-coding gene on chromosome 20q13.13, encoding Brefeldin A-inhibited guanine nucleotide-exchange protein 2 (Q9Y6D5). Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6.

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 and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition.

Source: NCBI Gene 10564 — RefSeq curated summary.

At a glance

• Gene–disease (curated): periventricular heterotopia with microcephaly, autosomal recessive (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 23
• Clinical variants (ClinVar): 879 total — 14 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_006420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15853
Approved symbol	ARFGEF2
Name	ARF guanine nucleotide exchange factor 2
Location	20q13.13
Locus type	gene with protein product
Status	Approved
Aliases	BIG2
Ensembl gene	ENSG00000124198
Ensembl biotype	protein_coding
OMIM	605371
Entrez	10564

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 retained_intron, 5 protein_coding, 4 nonsense_mediated_decay

ENST00000371917, ENST00000493140, ENST00000679436, ENST00000679542, ENST00000679747, ENST00000680130, ENST00000680635, ENST00000680871, ENST00000681021, ENST00000681119, ENST00000681399, ENST00000681656, ENST00000681885, ENST00000939861, ENST00000963182

RefSeq mRNA: 2 — MANE Select: NM_006420 NM_001410846, NM_006420

CCDS: CCDS13411, CCDS93055

Canonical transcript exons

ENST00000371917 — 39 exons

Exon	Start	End
ENSE00000845453	48941199	48941229
ENSE00000845454	48941864	48941987
ENSE00000845455	48951323	48951469
ENSE00000845456	48952705	48952884
ENSE00000845457	48953556	48953790
ENSE00000845458	48963830	48963898
ENSE00000845459	48965872	48966023
ENSE00000845460	48969147	48969277
ENSE00000845461	48971120	48971354
ENSE00000845462	48972326	48972425
ENSE00000845463	48973145	48973284
ENSE00000845465	48976016	48976199
ENSE00000845466	48984729	48984840
ENSE00000845467	48985408	48985613
ENSE00000845468	48988304	48988388
ENSE00000845470	48989285	48989436
ENSE00000845471	48989556	48989684
ENSE00000845473	48994451	48994598
ENSE00000845474	48995783	48995882
ENSE00000845475	48998193	48998233
ENSE00000845476	48998336	48998505
ENSE00000845478	49010232	49010404
ENSE00000845479	49011924	49012084
ENSE00000845480	49013564	49013694
ENSE00000845482	49016280	49016415
ENSE00000845483	49017249	49017387
ENSE00000845484	49017496	49017550
ENSE00000845485	49018884	49018998
ENSE00000845486	49023051	49023181
ENSE00000845487	49025313	49025481
ENSE00000845488	49028530	49028668
ENSE00000845489	49032049	49032166
ENSE00001456436	49033023	49036693
ENSE00001456459	48921711	48922010
ENSE00001593653	48991040	48991198
ENSE00001671877	49013831	49013960
ENSE00001673069	48988491	48988662
ENSE00001675491	48974766	48974874
ENSE00001763604	49005070	49005221

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 95.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.9578 / max 927.3328, expressed in 1818 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185142	46.9488	1818
185143	2.4858	1144
185144	1.1400	542
185145	0.2223	103
185141	0.1610	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	95.70	gold quality
jejunal mucosa	UBERON:0000399	95.41	gold quality
parotid gland	UBERON:0001831	95.05	gold quality
choroid plexus epithelium	UBERON:0003911	95.01	gold quality
upper leg skin	UBERON:0004262	94.89	gold quality
corpus epididymis	UBERON:0004359	94.89	gold quality
cardia of stomach	UBERON:0001162	94.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.29	gold quality
secondary oocyte	CL:0000655	94.18	gold quality
pigmented layer of retina	UBERON:0001782	94.15	gold quality
colonic mucosa	UBERON:0000317	94.04	gold quality
epithelium of nasopharynx	UBERON:0001951	94.04	gold quality
caput epididymis	UBERON:0004358	93.94	gold quality
skin of hip	UBERON:0001554	93.91	gold quality
adrenal tissue	UBERON:0018303	93.79	gold quality
tibia	UBERON:0000979	93.76	gold quality
mammary duct	UBERON:0001765	93.71	gold quality
jejunum	UBERON:0002115	93.63	gold quality
oral cavity	UBERON:0000167	93.46	gold quality
epithelium of mammary gland	UBERON:0003244	93.38	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.24	gold quality
postcentral gyrus	UBERON:0002581	93.19	gold quality
superficial temporal artery	UBERON:0001614	92.59	gold quality
renal medulla	UBERON:0000362	92.45	gold quality
parietal lobe	UBERON:0001872	92.18	gold quality
mammalian vulva	UBERON:0000997	92.15	gold quality
pons	UBERON:0000988	92.04	gold quality
lower lobe of lung	UBERON:0008949	92.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.78	gold quality
esophagus squamous epithelium	UBERON:0006920	91.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-97	no	149.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

184 targeting ARFGEF2, 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-9-5P	100.00	72.28	2361
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• involvement in molecular mechanisms of vesicular transport (PMID:11665623)
• identification of protein kinase A-anchoring domains (PMID:12571360)
• BIG2 and Exo70 interact in trans-Golgi network and centrosomes, as well as in exocyst structures or complexes that move along microtubules to the plasma membrane. (PMID:15705715)
• ARFGEF2 mRNA was widely expressed in all cortical layers, especially in the neural precursors of the ventricular and subventricular zones during development, with persistent but diminished expression in adulthood. (PMID:16320251)
• Regulates the constitutive release of tumor necrosis factor receptor type 1 exosome-like vesicles from vascular endothelial cells. (PMID:17276987)
• 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)
• 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)
• both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles occur via PKA-dependent pathways that are regulated by the anchoring of RIIbeta to BIG2 via AKAP domains B and C (PMID:18625701)
• Results describe a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations. (PMID:19384555)
• BIG1 and BIG2 have roles in endomembrane organization (PMID:20360857)
• Up-regulation of ARFGEF2 is associated with the Huntington’s disease. (PMID:21309479)
• Brefeldin A-inhibited ADP-ribosylation factor activator BIG2 regulates cell migration via integrin beta1 cycling and actin remodeling. (PMID:22908276)
• 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)
• The clinical phenotype associated with mutations in ARFGEF2 is relatively homogeneous in the families report. (PMID:23755938)
• Description of a novel ARFGEF2 mutation in five related patients presenting with West syndrome, microcephaly, periventricular heterotopia and thin corpus callosum. (PMID:23812912)
• 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)
• 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)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	arfgef2	ENSDARG00000074702
mus_musculus	Arfgef2	ENSMUSG00000074582
rattus_norvegicus	Arfgef2	ENSRNOG00000007485
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), ARFGEF1 (ENSG00000066777), CYTH4 (ENSG00000100055), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

Brefeldin A-inhibited guanine nucleotide-exchange protein 2 — Q9Y6D5 (reviewed: Q9Y6D5)

Alternative names: ADP-ribosylation factor guanine nucleotide-exchange factor 2

All UniProt accessions (7): A0A7P0T7Z2, A0A7P0T9L6, A0A7P0T9L9, A0A7P0TA34, A0A7P0TAV0, A0A7P0Z446, Q9Y6D5

UniProt curated annotations — full annotation on UniProt →

Function. Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.

Subunit / interactions. Homodimer. Interacts with ARFGEF1/BIG1; both proteins are probably part of the same or very similar macromolecular complexes. Interacts with PRKAR1A, PRKAR2A, PRKAR1B, PRKAR2B, PPP1CC, PDE3A, TNFRSF1A, MYCBP and EXOC7. Interacts with GABRB1, GABRB2 and GABRB3.

Subcellular location. Cytoplasm. Membrane. Golgi apparatus. Perinuclear region. trans-Golgi network. Endosome. Cytoskeleton. Microtubule organizing center. Centrosome. Cell projection. Dendrite. Cytoplasmic vesicle. Synapse.

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

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

Disease relevance. Periventricular nodular heterotopia 2 (PVNH2) [MIM:608097] A developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH2 is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with PVNH2. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by brefeldin A.

RefSeq proteins (2): NP_001397775, NP_006411* (*=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 (57 total): modified residue 20, helix 10, turn 6, region of interest 4, sequence variant 4, sequence conflict 4, mutagenesis site 3, strand 2, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3L8N	X-RAY DIFFRACTION	2.86
3SWV	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6D5-F1	77.59	0.41

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 (20): 218, 227, 244, 277, 348, 349, 614, 616, 617, 626, 700, 1511, 1513, 1514, 1525, 1528, 1534, 1782, 1, 214

Mutagenesis-validated functional residues (3):

Position	Phenotype
289	abolishes interaction with prkar2b and impairs tnfrsf1a release.
534	abolishes interaction with prkar2b and impairs tnfrsf1a release.
738	disturbs membrane organization at the tgn, impairs association of the ap-1 complex and gga1 with the tgn membranes.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-390466	Chaperonin-mediated protein folding
R-HSA-391251	Protein folding
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 307 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_ENDOSOME_ORGANIZATION, GOBP_VESICLE_ORGANIZATION, MORF_BRCA1, KENNY_CTNNB1_TARGETS_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, MORF_RAD51L3, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION, COUP_01, GOBP_EXOCYTOSIS, GOBP_GOLGI_TO_PLASMA_MEMBRANE_TRANSPORT

GO Biological Process (10): receptor recycling (GO:0001881), exocytosis (GO:0006887), Golgi to plasma membrane transport (GO:0006893), endosome organization (GO:0007032), endomembrane system organization (GO:0010256), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), regulation of ARF protein signal transduction (GO:0032012), positive regulation of tumor necrosis factor production (GO:0032760), intracellular signal transduction (GO:0035556)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), myosin binding (GO:0017022), protein kinase A regulatory subunit binding (GO:0034237), GABA receptor binding (GO:0050811), protein binding (GO:0005515)

GO Cellular Component (24): Golgi membrane (GO:0000139), trans-Golgi network (GO:0005802), centrosome (GO:0005813), microtubule organizing center (GO:0005815), cytosol (GO:0005829), axonemal microtubule (GO:0005879), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), asymmetric synapse (GO:0032279), symmetric synapse (GO:0032280), dendritic spine (GO:0043197), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737), endosome (GO:0005768), Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), dendrite (GO:0030425), cell projection (GO:0042995), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Protein folding	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	4
synapse	3
transport	2
intracellular anatomical structure	2
neuron to neuron synapse	2
endomembrane system	2
endocytosis	1
receptor metabolic process	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
post-Golgi vesicle-mediated transport	1
vesicle-mediated transport to the plasma membrane	1
endomembrane system organization	1
vesicle organization	1
cellular component organization	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
cytoskeletal protein binding	1
protein kinase A binding	1
signaling receptor binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
Golgi apparatus subcompartment	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1
cytoplasmic microtubule	1

Protein interactions and networks

STRING

1686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARFGEF2	FLNA	P21333	856
ARFGEF2	ERMARD	Q5T6L9	729
ARFGEF2	PPP1CC	P36873	642
ARFGEF2	DCHS1	Q96JQ0	619
ARFGEF2	ARF1	P10947	562
ARFGEF2	BCAS4	Q8TDM0	532
ARFGEF2	FAT4	Q6V0I7	525
ARFGEF2	ARF6	P26438	524
ARFGEF2	ITCH	Q96J02	502
ARFGEF2	FLNB	O75369	458
ARFGEF2	DCAKD	Q8WVC6	455
ARFGEF2	EXOC7	Q9UPT5	451
ARFGEF2	INTS8	Q75QN2	448
ARFGEF2	WDR62	O43379	446
ARFGEF2	RABIF	P47224	440

IntAct

148 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
ARFGEF2	MYCBP	psi-mi:“MI:0915”(physical association)	0.790
MYCBP	ARFGEF2	psi-mi:“MI:0915”(physical association)	0.790
MYCBP	ARFGEF2	psi-mi:“MI:0403”(colocalization)	0.790
TMEM9B	DNAJC13	psi-mi:“MI:0914”(association)	0.640
ARFGEF1	KANK1	psi-mi:“MI:0914”(association)	0.630
ARFGEF1	PDE3A	psi-mi:“MI:0914”(association)	0.580
MYCBP	AKAP8	psi-mi:“MI:0914”(association)	0.550
MADCAM1	TCAF2	psi-mi:“MI:0914”(association)	0.530
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
FAM131B	AURKA	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
NHLH2	AP3B1	psi-mi:“MI:0914”(association)	0.530
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530

BioGRID (188): ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Co-fractionation), ARFGEF2 (Affinity Capture-MS), ARFGEF2 (Co-localization), ARFGEF2 (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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 160 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
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	6	15.5×	4e-04
Regulation of activated PAK-2p34 by proteasome mediated degradation	5	14.5×	9e-04
SPOP-mediated proteasomal degradation of PD-L1(CD274)	6	14.3×	5e-04
Regulation of ornithine decarboxylase (ODC)	5	14.2×	9e-04
Vpu mediated degradation of CD4	5	13.8×	9e-04
Autodegradation of the E3 ubiquitin ligase COP1	5	13.8×	9e-04
Ubiquitin-dependent degradation of Cyclin D	5	13.8×	9e-04
Cross-presentation of soluble exogenous antigens (endosomes)	5	13.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	10
Uncertain significance	422
Likely benign	263
Benign	82

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1323380	NM_006420.3(ARFGEF2):c.1072C>T (p.Gln358Ter)	Pathogenic
1701422	NM_006420.3(ARFGEF2):c.1959_1966del (p.Phe654fs)	Pathogenic
1705394	NM_006420.3(ARFGEF2):c.4003G>T (p.Glu1335Ter)	Pathogenic
183282	NM_006420.3(ARFGEF2):c.656dup (p.Val220fs)	Pathogenic
2004841	NM_006420.3(ARFGEF2):c.562C>T (p.Gln188Ter)	Pathogenic
2652384	NM_006420.3(ARFGEF2):c.1308_1309dup (p.Cys437fs)	Pathogenic
3254661	NM_006420.3(ARFGEF2):c.4918C>T (p.Arg1640Ter)	Pathogenic
3685437	NM_006420.3(ARFGEF2):c.1421_1424dup (p.Glu475fs)	Pathogenic
3728317	NM_006420.3(ARFGEF2):c.1459G>T (p.Glu487Ter)	Pathogenic
434297	NM_006420.3(ARFGEF2):c.2638_2639delinsT (p.Pro880fs)	Pathogenic
803610	NM_006420.3(ARFGEF2):c.1492del (p.Met498fs)	Pathogenic
803611	NM_006420.3(ARFGEF2):c.5254C>T (p.Arg1752Ter)	Pathogenic
89028	NM_006420.3(ARFGEF2):c.1958+1G>A	Pathogenic
985292	NM_006420.3(ARFGEF2):c.3758-2A>C	Pathogenic
191316	Single allele	Likely pathogenic
2023723	NM_006420.3(ARFGEF2):c.4050-2A>T	Likely pathogenic
2434911	NM_006420.3(ARFGEF2):c.2821C>T (p.Arg941Ter)	Likely pathogenic
2585457	NM_006420.3(ARFGEF2):c.91C>T (p.Gln31Ter)	Likely pathogenic
377213	NM_006420.3(ARFGEF2):c.3169C>T (p.Gln1057Ter)	Likely pathogenic
4278356	NM_006420.3(ARFGEF2):c.3487C>T (p.Gln1163Ter)	Likely pathogenic
4293168	NM_006420.3(ARFGEF2):c.1346dup (p.Pro449_Asp450insTer)	Likely pathogenic
817984	NM_006420.3(ARFGEF2):c.4059dup (p.Val1354fs)	Likely pathogenic
930714	NM_006420.3(ARFGEF2):c.4269del (p.Leu1424fs)	Likely pathogenic
977323	NM_006420.3(ARFGEF2):c.4455-1G>A	Likely pathogenic

SpliceAI

5429 predictions. Top by Δscore:

Variant	Effect	Δscore
20:48921956:G:GT	donor_gain	1.0000
20:48949131:G:T	donor_gain	1.0000
20:48951317:CTTTA:C	acceptor_loss	1.0000
20:48951318:TTTA:T	acceptor_loss	1.0000
20:48951321:A:AG	acceptor_gain	1.0000
20:48951321:AGA:A	acceptor_loss	1.0000
20:48951322:G:GA	acceptor_gain	1.0000
20:48951322:GA:G	acceptor_gain	1.0000
20:48951322:GAA:G	acceptor_gain	1.0000
20:48951322:GAAA:G	acceptor_gain	1.0000
20:48951467:AAGGT:A	donor_loss	1.0000
20:48951468:AGG:A	donor_loss	1.0000
20:48951469:GGTAT:G	donor_loss	1.0000
20:48951470:G:GC	donor_loss	1.0000
20:48951471:T:G	donor_loss	1.0000
20:48963811:T:G	acceptor_gain	1.0000
20:48963812:ATTT:A	acceptor_gain	1.0000
20:48963812:ATTTG:A	acceptor_gain	1.0000
20:48963825:TGTA:T	acceptor_loss	1.0000
20:48963827:TA:T	acceptor_loss	1.0000
20:48963828:A:AC	acceptor_loss	1.0000
20:48963828:A:AG	acceptor_gain	1.0000
20:48963828:AG:A	acceptor_gain	1.0000
20:48963828:AGG:A	acceptor_gain	1.0000
20:48963829:G:GT	acceptor_gain	1.0000
20:48963829:GG:G	acceptor_gain	1.0000
20:48963829:GGG:G	acceptor_gain	1.0000
20:48963829:GGGA:G	acceptor_gain	1.0000
20:48963829:GGGAC:G	acceptor_gain	1.0000
20:48963895:AAAGG:A	donor_loss	1.0000

AlphaMissense

11855 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:48941974:T:C	L88P	1.000
20:48951327:T:C	L94P	1.000
20:48951469:G:C	K141N	1.000
20:48951469:G:T	K141N	1.000
20:48952709:T:C	L143P	1.000
20:48952712:T:C	L144P	1.000
20:48952798:A:C	S173R	1.000
20:48952800:C:A	S173R	1.000
20:48952800:C:G	S173R	1.000
20:48952825:G:C	A182P	1.000
20:48952826:C:A	A182D	1.000
20:48952838:T:C	L186P	1.000
20:48969204:G:C	D373H	1.000
20:48969229:T:C	L381P	1.000
20:48969231:T:C	C382R	1.000
20:48969232:G:A	C382Y	1.000
20:48969233:C:G	C382W	1.000
20:48969238:T:C	L384P	1.000
20:48971141:G:C	K404N	1.000
20:48971141:G:T	K404N	1.000
20:48971152:T:C	L408P	1.000
20:48971158:T:C	L410P	1.000
20:48971161:T:C	L411P	1.000
20:48971236:T:C	L436P	1.000
20:48971238:T:C	C437R	1.000
20:48971240:T:G	C437W	1.000
20:48971258:C:A	N443K	1.000
20:48971258:C:G	N443K	1.000
20:48971260:G:A	G444D	1.000
20:48971314:T:C	L462P	1.000

dbSNP variants (sampled 300 via entrez): RS1000005486 (20:48969477 A>C,G), RS1000008128 (20:48925625 C>A), RS1000012770 (20:48951114 G>A,T), RS1000020824 (20:48941304 C>G,T), RS1000141062 (20:48928684 C>T), RS1000165477 (20:49021346 T>C,G), RS1000185512 (20:48992535 G>A), RS1000212945 (20:48931677 A>AG), RS1000216671 (20:48992160 C>T), RS1000241287 (20:48948399 A>G), RS1000253159 (20:48972801 C>A,G,T), RS1000267865 (20:48963170 T>C,G), RS1000272393 (20:49027388 C>G,T), RS1000300349 (20:49035886 T>G), RS1000302909 (20:48983029 T>C)

Disease associations

OMIM: gene MIM:605371 | disease phenotypes: MIM:608097, MIM:616056

GenCC curated gene-disease

Disease	Classification	Inheritance
periventricular heterotopia with microcephaly, autosomal recessive	Strong	Autosomal recessive
periventricular nodular heterotopia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
periventricular heterotopia with microcephaly, autosomal recessive	Definitive	AR

Mondo (6): periventricular heterotopia with microcephaly, autosomal recessive (MONDO:0011966), hydrocephalus (MONDO:0001150), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), developmental and epileptic encephalopathy, 26 (MONDO:0014477), periventricular nodular heterotopia (MONDO:0020341)

Orphanet (3): Nodular neuronal heterotopia (Orphanet:2149), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000817	Reduced eye contact
HP:0000963	Thin skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001643	Patent ductus arteriosus
HP:0001654	Abnormal heart valve morphology
HP:0001659	Aortic regurgitation
HP:0001892	Abnormal bleeding
HP:0002020	Gastroesophageal reflux
HP:0002021	Pyloric stenosis
HP:0002079	Hypoplasia of the corpus callosum
HP:0002273	Tetraparesis
HP:0002521	Hypsarrhythmia
HP:0002650	Scoliosis
HP:0002999	Patellar dislocation
HP:0003593	Infantile onset
HP:0003834	Shoulder dislocation
HP:0004942	Aortic aneurysm
HP:0007165	Periventricular heterotopia
HP:0007359	Focal-onset seizure
HP:0010864	Severe intellectual disability
HP:0012639	Abnormal nervous system morphology

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002324_11	Anger	7.000000e-06
GCST004500_120	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-09
GCST004501_28	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-09
GCST004504_7	Waist circumference adjusted for BMI in non-smokers	3.000000e-06
GCST005316_240	Intelligence (MTAG)	1.000000e-13
GCST005316_241	Intelligence (MTAG)	6.000000e-15
GCST005316_244	Intelligence (MTAG)	4.000000e-12
GCST005316_248	Intelligence (MTAG)	3.000000e-10
GCST005316_250	Intelligence (MTAG)	7.000000e-16
GCST005316_295	Intelligence (MTAG)	2.000000e-08
GCST005316_429	Intelligence (MTAG)	4.000000e-11
GCST006269_1082	General cognitive ability	3.000000e-11
GCST006269_737	General cognitive ability	1.000000e-08
GCST006923_15	Loneliness	3.000000e-08
GCST006924_7	Loneliness (MTAG)	3.000000e-09
GCST007044_24	Extremely high intelligence	7.000000e-10
GCST008163_183	Height	1.000000e-07
GCST008362_70	Birth weight	2.000000e-08
GCST008363_132	Offspring birth weight	3.000000e-08
GCST010988_327	Adult body size	3.000000e-12
GCST012226_839	Waist circumference adjusted for body mass index	5.000000e-08
GCST012227_1114	Hip circumference adjusted for BMI	6.000000e-10
GCST012227_1115	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0003015	aggressive behavior
EFO:0004318	smoking behavior
EFO:0007789	BMI-adjusted waist circumference
EFO:0004337	intelligence
EFO:0007865	loneliness measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006849	Hydrocephalus	C10.228.140.602
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D054091	Periventricular Nodular Heterotopia	C10.500.507.450.750; C16.131.666.507.450.750
C564292	Heterotopia, Periventricular, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105732 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases abundance, affects expression, increases expression	3
Cyclosporine	increases expression	3
sodium arsenite	decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
ginger extract	affects expression, increases abundance, affects cotreatment	1
2,4,6-tribromophenol	decreases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol B	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Rosiglitazone	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Coumestrol	decreases expression	1
Clodronic Acid	affects expression	1
Ibuprofen	increases expression	1
Ivermectin	decreases expression	1
Latex	increases 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
CHEMBL4012589	Binding	Binding affinity to BIG2 protein in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01323764	PHASE4	COMPLETED	ShuntCheck Versus Radionuclide in Evaluating Shunt Function in Symptomatic NPH Patients
NCT01685450	PHASE4	UNKNOWN	NIMIP: Non Invasive Measurement of the Intracranial Pressure
NCT03513757	PHASE4	COMPLETED	Dexmedetomidine and Propofol for Pediatric MRI Sedation
NCT07547826	PHASE4	NOT_YET_RECRUITING	Efficacy and Cost-Effectiveness of Topical Vancomycin Powder in Preventing Pediatric Ventriculoperitoneal Shunt Infections Across Different Etiologies
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00196196	PHASE3	COMPLETED	A Precision and Accuracy Study of the Codman Valve Position Verification (VPV) System.
NCT00286104	PHASE3	COMPLETED	Impact of Ventricular Catheter Used With Antimicrobial Agents on Patients With a Ventricular Catheter
NCT01936272	PHASE3	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Shunt vs ETV/CPC for PIH in Ugandan Infants
NCT02425761	PHASE3	UNKNOWN	The CSF Shunt Entry Site Trial
NCT02512809	PHASE3	TERMINATED	Isoflurane-induced Neuroinflammation in Children With Hydrocephalus
NCT04177914	PHASE3	RECRUITING	HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00652470	PHASE2	COMPLETED	A Study Comparing Two Treatments for Infants With Hydrocephalus
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05001750	PHASE1	RECRUITING	Prophylactic Antibiotics Useful With Antibiotic Impregnated External Ventricular Drains (EVDs)?
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.
NCT01878136	PHASE1/PHASE2	WITHDRAWN	Effect of Intraventricular tPA Following Aneurysmal Subarachnoid Hemorrhage
NCT05476874	PHASE1/PHASE2	UNKNOWN	Improvement of Peritoneal Catheter Placement in VPS With a Splitable Trocar
NCT00001327	Not specified	COMPLETED	Establishing the Physiology of Syringomyelia
NCT00280904	Not specified	COMPLETED	A Registry for Comparing Catheter-Related Infection Rates Among Various Shunt Systems in the Treatment of Hydrocephalus
NCT00651950	Not specified	WITHDRAWN	Bench Study of Transcutaneous Hydrocephalic Shunt Flow Sensor Alignment Accuracy and Repeatability
NCT00652197	Not specified	COMPLETED	Monitoring Patient Cerebro-Spinal Fluid Drainage With an Ultrasonic Flow Sensor
NCT00652249	Not specified	WITHDRAWN	Diagnosing Malfunctioning Hydrocephalic Shunt Valves With a Flow Sensor
NCT00692744	Not specified	COMPLETED	Quality of Life in Elderly After Aneurysmal Subarachnoid Hemorrhage (SAH)
NCT00743457	Not specified	COMPLETED	Study of Ultrasound of the Eye for Children With Suspected Shunt Failure
NCT00875758	Not specified	COMPLETED	Optimizing Treatment of Post-hemorrhagic Ventricular Dilation in Preterm Infants
NCT00886054	Not specified	UNKNOWN	The Prediction of Intracranial Pressure and Clinical Outcome by Transcranial Doppler in Neurocritical Patients
NCT00946127	Not specified	TERMINATED	ETV Versus Shunt Surgery in Normal Pressure Hydrocephalus
NCT01108965	Not specified	COMPLETED	Study of Shunt Flow Sensor Accuracy in Extra-ventricular Drains.