CYTH2

Summary

CYTH2 (cytohesin 2, HGNC:9502) is a protein-coding gene on chromosome 19q13.33, encoding Cytohesin-2 (Q99418). Acts as a guanine-nucleotide exchange factor (GEF).

The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family appear to mediate the regulation of protein sorting and membrane trafficking. The encoded protein exhibits GEP activity in vitro with ARF1, ARF3, and ARF6 and is 83% homologous to CYTH1. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9266 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 51 total
• Druggable target: yes
• MANE Select transcript: NM_004228

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9502
Approved symbol	CYTH2
Name	cytohesin 2
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	CTS18.1, Sec7p-L, ARNO, Sec7p-like, cytohesin-2
Ensembl gene	ENSG00000105443
Ensembl biotype	protein_coding
OMIM	602488
Entrez	9266

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000325139, ENST00000391881, ENST00000427476, ENST00000452733, ENST00000460595, ENST00000462117, ENST00000467412, ENST00000474049, ENST00000474209, ENST00000493260, ENST00000595765, ENST00000600597, ENST00000641098, ENST00000704950

RefSeq mRNA: 2 — MANE Select: NM_004228 NM_004228, NM_017457

CCDS: CCDS12722, CCDS86786

Canonical transcript exons

ENST00000452733 — 12 exons

Exon	Start	End
ENSE00001833864	48469369	48469526
ENSE00003061124	48479123	48482314
ENSE00003641238	48478069	48478145
ENSE00003716163	48470353	48470500
ENSE00003719343	48473298	48473378
ENSE00003722687	48470603	48470669
ENSE00003723310	48473905	48474017
ENSE00003726384	48472325	48472443
ENSE00003738301	48478438	48478592
ENSE00003745390	48478275	48478346
ENSE00003746431	48474838	48474949
ENSE00003788775	48474182	48474330

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.1648 / max 465.2137, expressed in 1825 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176795	42.8873	1824
176794	6.7581	1782
176792	0.7599	466
176793	0.6988	439
176791	0.0480	4
176796	0.0127	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.48	gold quality
cortical plate	UBERON:0005343	97.35	gold quality
left testis	UBERON:0004533	97.11	gold quality
right testis	UBERON:0004534	97.10	gold quality
frontal pole	UBERON:0002795	96.98	gold quality
right lobe of thyroid gland	UBERON:0001119	96.81	gold quality
left lobe of thyroid gland	UBERON:0001120	96.81	gold quality
paraflocculus	UBERON:0005351	96.80	gold quality
thyroid gland	UBERON:0002046	96.37	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.74	gold quality
middle frontal gyrus	UBERON:0002702	95.49	gold quality
lower esophagus mucosa	UBERON:0035834	95.13	gold quality
testis	UBERON:0000473	95.09	gold quality
ventricular zone	UBERON:0003053	95.00	gold quality
gall bladder	UBERON:0002110	94.87	gold quality
endocervix	UBERON:0000458	94.82	gold quality
minor salivary gland	UBERON:0001830	94.76	gold quality
popliteal artery	UBERON:0002250	94.69	gold quality
tibial artery	UBERON:0007610	94.69	gold quality
metanephros cortex	UBERON:0010533	94.69	gold quality
prefrontal cortex	UBERON:0000451	94.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.59	gold quality
skin of leg	UBERON:0001511	94.35	gold quality
aorta	UBERON:0000947	94.28	gold quality
skin of abdomen	UBERON:0001416	94.28	gold quality
adenohypophysis	UBERON:0002196	94.20	gold quality
body of stomach	UBERON:0001161	94.15	gold quality
sural nerve	UBERON:0015488	93.95	gold quality
ascending aorta	UBERON:0001496	93.86	gold quality
mucosa of stomach	UBERON:0001199	93.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.87
E-GEOD-93593	yes	6.69
E-MTAB-8060	no	85.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting CYTH2, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-6892-3P	99.68	66.40	1178

Literature-anchored findings (GeneRIF, showing 29)

• The overexpression of ARNO, another mammalian GEF, produces extensive neuritogenesis in Aplysia neurons (PMID:12641750)
• cytohesin 2 binds to IPCEF1, which modifies its activity (PMID:12920129)
• the N-terminal coiled-coil and parts of the Sec7 domain of cytohesin-2 are required for serum-mediated transcriptional activation in nonimmune cells (PMID:15277685)
• Endogenous levels of ARNO/cytohesin-2 present in HEK293 cells are sufficient and necessary for sustained activation of the MAP kinase signaling pathway (PMID:16027149)
• The transport and regulation of ARNO in polartized epithelial cells, and its interactions with ARF6 in endocytosis are reported. (PMID:16484220)
• Study shows that three related Arf-like GTPases Arl4a, Arl4c, and Arl4d, are able to recruit ARNO and other cytohesins to the plasma membrane by binding to their PH domains irrespective of whether they are in the diglycine or triglycine form. (PMID:17398095)
• data suggest cells ruffle upon CaSR (calcium sensing receptor)stimulation via a mechanism that involves translocation of beta-arrestin 1 pre-assembled with the CaSR or ARNO (Arf nucleotide binding site opener) (PMID:17623778)
• protein-protein interaction mediated by ARNO coiled-coil domain required for ARNO induced motility; coiled-coil domain promotes assembly of multiprotein complex containing ARNO and Dock180; assembly of complex requires coiled-coil domain, GRASP and IPCEF (PMID:20016009)
• Specific motifs of the V-ATPase a2-subunit isoform interact with catalytic and regulatory domains of ARNO. (PMID:20153292)
• cytohesin-2, through a previously unexplored complex formation with paxillin, regulates preadipocyte migration; paxillin plays a previously unknown role as a scaffold protein of Arf guanine-nucleotide exchange factor (PMID:20525696)
• Arno behaves as a bistable switch, having an absolute requirement for activation by an Arf protein but, once triggered, becoming highly active through the positive feedback effect of Arf1-GTP. (PMID:21118813)
• Data that aldolase forms a complex with ARNO/Arf6 and the V-ATPase and that it may contribute to remodeling of the actin cytoskeleton. (PMID:21307348)
• role for endothelial ARNO in VEGF-dependent initiation of angiogenesis by regulation of VEGFR-2 internalization in endothelial cells, resulting in the activation of the Akt pathway, vessel permeability, and ultimately endothelial proliferation (PMID:22002459)
• ARNO in turn triggered WAVE regulatory complex recruitment and activation, which was dramatically enhanced when ARNO cooperated with Salmonella SopE. (PMID:22341462)
• The PH domains of cytohesin 2/ARNO and cytohesin 3/GRP1 are responsible for the differential effects of these proteins on cell adhesion to fibronectin. (PMID:22454518)
• Expression of CYTH2 mutant deficient of the EFh2 domain in cells also inhibits Arf6 activation and neurite extension. (PMID:22659138)
• Arf6/ ARNO signaling mediates phospholipase-D, ERK1/2 and cofilin activation in pancreatic beta-cells. (PMID:23095975)
• Kinetics of interaction between ADP-ribosylation factor-1 (Arf1) and the Sec7 domain of Arno guanine nucleotide exchange factor, modulation by allosteric factors, and the uncompetitive inhibitor brefeldin A (PMID:23255605)
• The N termini of a-subunit isoforms are involved in signaling between vacuolar H+-ATPase (V-ATPase) and cytohesin-2 (PMID:23288846)
• There is an association between cytohesin-2 expression and overall survival and disease-free survival in patients with hepatocellular carcinoma. (PMID:23545718)
• Phosphorylation of Ser392 of ARNO stabilized the C-terminal alpha-helix via formation of salt bridges between phospho-Ser392 and Arg390, Lys395, and Lys396. (PMID:24083777)
• Cytohesin-2 constitutively suppresses platelet dense granule secretion and aggregation by keeping ARF6 in a GTP-bound state (PMID:24581425)
• inhibiting cytohesins or ARNO as cytoplasmic activators of EGFR and IGF-I in colorectal cancer resulted in anti-proliferation, reduced invasion, decreased migration, and suppressed growth in vivo and in vitro. (PMID:24618737)
• The authors show that Shigella flexneri IpgD phosphatase activity is required for recruitment of the ARF6 guanine nucleotide exchange factor (GEF) ARF nucleotide binding site opener (ARNO) to bacterial entry sites. (PMID:25736891)
• Data establish a role for cytohesin-2/ARNO as a regulator of R-Ras and integrin recycling and suggest that ARF-regulated trafficking of R-Ras is required for R-Ras-dependent effects on spreading and adhesion formation. (PMID:26378252)
• Authors’ experiments argue against ARNO being a robust modifier of EGFR catalytic activity. (PMID:27203102)
• ARNO-ARF1 regulates formation of podosomes by inhibition of RhoA/myosin-II and promotion of actin core assembly. (PMID:28007915)
• INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation. (PMID:30355448)
• Molecular Architecture of a Network of Potential Intracellular EGFR Modulators: ARNO, CaM, Phospholipids, and the Juxtamembrane Segment. (PMID:31780432)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyth2	ENSDARG00000028800
mus_musculus	Cyth2	ENSMUSG00000003269
rattus_norvegicus	Cyth2	ENSRNOG00000021051
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), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

Cytohesin-2 — Q99418 (reviewed: Q99418)

Alternative names: ARF exchange factor, ARF nucleotide-binding site opener, PH, SEC7 and coiled-coil domain-containing protein 2

All UniProt accessions (7): Q99418, A0A0D9SFG6, A0A286YF81, A0A994J5E5, F8W8E2, G5E9B7, M0R2J0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine-nucleotide exchange factor (GEF). Promotes guanine-nucleotide exchange on ARF1, ARF3 and ARF6. Activates ARF factors through replacement of GDP with GTP. The cell membrane form, in association with ARL4 proteins, recruits ARF6 to the plasma membrane. Involved in neurite growth.

Subunit / interactions. Heteromer. Composed of TAMALIN, CYTH2 and at least one GRM1. Interacts with ARRB1. Interacts with ARL4D; the interaction is direct. Directly interacts with CCDC120 through the coiled coil domain; this interaction stabilizes CCDC120, possibly by preventing its ubiquitination, and is required for neurite growth in neuroblastoma cells. Interacts with ARF1. Interacts with FRMD4A. Interacts (via N-terminal domain) with INAVA (via N-terminal domain).

Subcellular location. Cell membrane. Cytoplasm. Cell projection. Growth cone. Cell junction. Tight junction. Adherens junction.

Tissue specificity. Widely expressed.

Domain organisation. Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate. The PH domain is necessary and sufficient for plasma membrane relocalization. Autoinhibited by its C-terminal basic region. The coiled coil domain is involved in interaction with CCDC120.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99418-1	1	yes
Q99418-2	2

RefSeq proteins (2): NP_004219, NP_059431 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000904	Sec7_dom	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR023394	Sec7_C_sf	Homologous_superfamily
IPR035999	Sec7_dom_sf	Homologous_superfamily

Pfam: PF00169, PF01369

UniProt features (32 total): helix 10, binding site 7, mutagenesis site 5, domain 2, strand 2, chain 1, splice variant 1, sequence conflict 1, turn 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1R8S	X-RAY DIFFRACTION	1.46
4JXH	X-RAY DIFFRACTION	1.47
4JMI	X-RAY DIFFRACTION	1.5
1R8M	X-RAY DIFFRACTION	1.7
1S9D	X-RAY DIFFRACTION	1.8
4JMO	X-RAY DIFFRACTION	1.8
4L5M	X-RAY DIFFRACTION	1.8
1R8Q	X-RAY DIFFRACTION	1.86
4JWL	X-RAY DIFFRACTION	1.95
1PBV	X-RAY DIFFRACTION	2
4Z21	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99418-F1	85.02	0.46

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 (7): 350; 351; 268–276; 280; 291; 301; 339

Mutagenesis-validated functional residues (5):

Position	Phenotype
156	inhibits gtp gdp exchange activity. abolishes recruitment of arf6 to the plasma membrane.
268	does not reduce arl4d gtp-dependent interaction but inhibits targeting to the plasma membrane mediated by arl4c, arl4c a
280	does not reduce arl4d gtp-dependent interaction but inhibits targeting to the plasma membrane mediated by arl4c, arl4c a
303	reduces arl4d gtp-dependent interaction and targeting to the plasma membrane mediated by arl4c, arl4c and arl4d.
336	reduces arl4d gtp-dependent interaction and targeting to the plasma membrane mediated by arl4c, arl4c and arl4d.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6811438	Intra-Golgi traffic

MSigDB gene sets: 176 (showing top): CCAWYNNGAAR_UNKNOWN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, PID_PI3KCI_PATHWAY, GOCC_NEURON_PROJECTION, GOCC_CELL_CELL_JUNCTION, GOBP_IMPORT_INTO_CELL, DANG_BOUND_BY_MYC, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_ENDOCYTOSIS, ALCALA_APOPTOSIS

GO Biological Process (3): endocytosis (GO:0006897), actin cytoskeleton organization (GO:0030036), regulation of ARF protein signal transduction (GO:0032012)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), lipid binding (GO:0008289), inositol 1,4,5 trisphosphate binding (GO:0070679), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), membrane (GO:0016020), growth cone (GO:0030426), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
cytoskeleton organization	1
actin filament-based process	1
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
anion binding	1
alcohol binding	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
cell-cell junction	1
apical junction complex	1
tight junction	1
site of polarized growth	1
distal axon	1
cell junction	1

Protein interactions and networks

STRING

636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYTH2	TAMALIN	Q7Z6J2	981
CYTH2	ARF1	P10947	950
CYTH2	ARF6	P26438	943
CYTH2	ARL4A	P40617	822
CYTH2	TRIM23	P36406	797
CYTH2	G9CGD6	G9CGD6	737
CYTH2	PLEK2	Q9NYT0	721
CYTH2	RABIF	P47224	720
CYTH2	ARL4D	P49703	718
CYTH2	PLEK	P08567	716
CYTH2	CDKN2A	P42771	710
CYTH2	ITGB2	P05107	700
CYTH2	FRMD4A	Q9P2Q2	657
CYTH2	DOCK1	Q14185	644
CYTH2	CCDC120	Q96HB5	643

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CCDC120	CYTH2	psi-mi:“MI:0915”(physical association)	0.800
ATP5IF1	ATP5F1B	psi-mi:“MI:0914”(association)	0.740
ARF1	CYTH2	psi-mi:“MI:0407”(direct interaction)	0.720
CYTH2	ARF1	psi-mi:“MI:0915”(physical association)	0.720
INAVA	CYTH2	psi-mi:“MI:0915”(physical association)	0.710
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
CCDC120	CYTH2	psi-mi:“MI:0915”(physical association)	0.670
CYTH2	CCDC120	psi-mi:“MI:0915”(physical association)	0.670
IPCEF1	CYTH2	psi-mi:“MI:0915”(physical association)	0.670
CNKSR1	CYTH2	psi-mi:“MI:0915”(physical association)	0.670
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
ADORA2A	CYTH2	psi-mi:“MI:0915”(physical association)	0.630
ADORA2A	CYTH2	psi-mi:“MI:0407”(direct interaction)	0.630
ADORA2A	CYTH2	psi-mi:“MI:0403”(colocalization)	0.630
ADORA2A	CYTH2	psi-mi:“MI:2364”(proximity)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610

BioGRID (90): CCDC120 (Two-hybrid), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CCDC120 (Two-hybrid), CYTH2 (PCA), CYTH2 (Two-hybrid), ADORA2A (Reconstituted Complex), CYTH2 (Affinity Capture-Western), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q1LSX9, A2A5R2, A2ALK8, A2APV2, D4A631, G3X9K3, G5EBH0, O08967, O43739, O46382, P26675, P42338, P52735, P63034, P63035, P97694, P97696, Q07139, Q15111, Q15438, Q2KI41, Q32NH8, Q3USB7, Q3UYK3, Q4KWH5, Q4KWH8, Q5SVR0, Q60992, Q62688, Q66K14, Q6NXC0, Q6ZPF4, Q6ZT07, Q76MY7, Q76MZ1, Q7TSU1, Q80YW0, Q8IVF7, Q8K394, Q8K4M9

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

5 interactions.

A	Effect	B	Mechanism
PRKCA	“down-regulates activity”	CYTH2	phosphorylation
PRKCB	“down-regulates activity”	CYTH2	phosphorylation
PRKCG	“down-regulates activity”	CYTH2	phosphorylation
CYTH2	up-regulates	Neurite_outgrowth
CYTH2	“up-regulates activity”	ARF6	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	13.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
insulin receptor signaling pathway	5	22.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1940 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48470343:C:A	acceptor_gain	1.0000
19:48470349:CTA:C	acceptor_loss	1.0000
19:48470351:A:AG	acceptor_gain	1.0000
19:48470351:A:G	acceptor_loss	1.0000
19:48470352:G:GT	acceptor_gain	1.0000
19:48470352:GA:G	acceptor_gain	1.0000
19:48470352:GAA:G	acceptor_gain	1.0000
19:48470352:GAAC:G	acceptor_gain	1.0000
19:48470352:GAACC:G	acceptor_gain	1.0000
19:48470451:C:G	donor_gain	1.0000
19:48470499:AG:A	donor_loss	1.0000
19:48470502:T:A	donor_loss	1.0000
19:48470592:T:TA	acceptor_gain	1.0000
19:48470601:A:AG	acceptor_gain	1.0000
19:48470602:G:GA	acceptor_gain	1.0000
19:48470602:GT:G	acceptor_gain	1.0000
19:48470602:GTA:G	acceptor_gain	1.0000
19:48470602:GTAA:G	acceptor_gain	1.0000
19:48472320:A:AG	acceptor_gain	1.0000
19:48472320:ACCAG:A	acceptor_gain	1.0000
19:48472321:C:G	acceptor_gain	1.0000
19:48472322:CA:C	acceptor_loss	1.0000
19:48472323:A:AG	acceptor_gain	1.0000
19:48472323:AG:A	acceptor_gain	1.0000
19:48472323:AGG:A	acceptor_gain	1.0000
19:48472323:AGGG:A	acceptor_gain	1.0000
19:48472324:G:A	acceptor_gain	1.0000
19:48472324:G:GT	acceptor_gain	1.0000
19:48472324:GGG:G	acceptor_gain	1.0000
19:48472324:GGGG:G	acceptor_gain	1.0000

AlphaMissense

2638 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48470637:G:C	G68R	1.000
19:48470638:G:A	G68D	1.000
19:48470649:T:C	F72L	1.000
19:48470650:T:C	F72S	1.000
19:48470651:C:A	F72L	1.000
19:48470651:C:G	F72L	1.000
19:48470654:C:A	N73K	1.000
19:48470654:C:G	N73K	1.000
19:48472325:G:A	G79R	1.000
19:48472325:G:C	G79R	1.000
19:48472325:G:T	G79W	1.000
19:48472326:G:A	G79E	1.000
19:48472380:C:A	A97D	1.000
19:48472389:T:C	L100P	1.000
19:48472407:T:C	L106P	1.000
19:48472412:A:G	K108E	1.000
19:48472414:G:C	K108N	1.000
19:48472414:G:T	K108N	1.000
19:48472422:T:A	I111N	1.000
19:48472424:G:A	G112R	1.000
19:48472424:G:C	G112R	1.000
19:48472424:G:T	G112W	1.000
19:48472425:G:A	G112E	1.000
19:48472425:G:T	G112V	1.000
19:48472434:T:C	L115P	1.000
19:48472436:G:A	G116R	1.000
19:48472436:G:C	G116R	1.000
19:48472436:G:T	G116W	1.000
19:48472437:G:A	G116E	1.000
19:48472437:G:T	G116V	1.000

dbSNP variants (sampled 300 via entrez): RS1000002285 (19:48475466 A>G), RS1000448683 (19:48474318 G>A,T), RS1000557685 (19:48480426 T>C), RS1000656313 (19:48477991 C>T), RS1000727176 (19:48479531 G>A), RS1000740354 (19:48468730 G>T), RS1000781827 (19:48473194 G>A), RS1000943199 (19:48478268 T>G), RS1001241217 (19:48469105 T>C,G), RS1001302236 (19:48470122 C>A,T), RS1001629518 (19:48474634 C>T), RS1001708783 (19:48479499 C>T), RS1002013971 (19:48473005 G>A), RS1002016848 (19:48472039 G>A), RS1002155498 (19:48477729 C>G,T)

Disease associations

OMIM: gene MIM:602488 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009303_11	Abstraction and mental flexibility	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009332	executive function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5995 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	8
Acetaminophen	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Cisplatin	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases expression	2
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Coumestrol	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Dronabinol	decreases expression	1
Thiram	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2445612	Binding	Inhibition of human Arno Sec7 domain binding to immobilized delta17 Arf1 (17 to 181) at 1 mM after 15 mins by BODIPY-GTP based time resolved fluorescence assay relative to control	Fragment-based identification of a locus in the Sec7 domain of Arno for the design of protein-protein interaction inhibitors. — J Med Chem

Clinical trials (associated diseases)

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