CYTH4

Summary

CYTH4 (cytohesin 4, HGNC:9505) is a protein-coding gene on chromosome 22q13.1, encoding Cytohesin-4 (Q9UIA0). Promotes guanine-nucleotide exchange on ARF1 and ARF5.

This gene encodes a member of the PSCD family of proteins, which have 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 function as GEPs for ADP-ribosylation factors (ARFs), which are guanine nucleotide-binding proteins involved in vesicular trafficking pathways. This protein exhibits GEP activity in vitro with ARF1 and ARF5, but is inactive with ARF6. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 27128 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_013385

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9505
Approved symbol	CYTH4
Name	cytohesin 4
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	CYT4, cytohesin-4
Ensembl gene	ENSG00000100055
Ensembl biotype	protein_coding
OMIM	606514
Entrez	27128

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000248901, ENST00000402997, ENST00000405206, ENST00000439667, ENST00000446506, ENST00000447919, ENST00000457992, ENST00000462927, ENST00000467664, ENST00000469886, ENST00000480510, ENST00000868416

RefSeq mRNA: 2 — MANE Select: NM_013385 NM_001318024, NM_013385

CCDS: CCDS13946

Canonical transcript exons

ENST00000248901 — 13 exons

Exon	Start	End
ENSE00001599019	37311456	37311527
ENSE00001651015	37312020	37312174
ENSE00001842701	37282508	37282588
ENSE00003459141	37299226	37299306
ENSE00003470219	37300907	37301019
ENSE00003506301	37313439	37315341
ENSE00003517736	37294660	37294724
ENSE00003519453	37310988	37311064
ENSE00003526372	37309212	37309323
ENSE00003542766	37303254	37303402
ENSE00003550611	37295999	37296065
ENSE00003644686	37292621	37292703
ENSE00003785052	37297564	37297682

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 98.91.

FANTOM5 (CAGE): breadth broad, TPM avg 20.9321 / max 1315.2597, expressed in 549 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192125	16.9014	535
192126	3.9057	392
192124	0.1250	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.91	gold quality
monocyte	CL:0000576	98.02	gold quality
mononuclear cell	CL:0000842	97.84	gold quality
leukocyte	CL:0000738	97.83	gold quality
blood	UBERON:0000178	97.64	gold quality
spleen	UBERON:0002106	95.28	gold quality
vermiform appendix	UBERON:0001154	93.67	gold quality
lymph node	UBERON:0000029	92.76	gold quality
periodontal ligament	UBERON:0008266	91.51	gold quality
bone marrow cell	CL:0002092	90.80	gold quality
gall bladder	UBERON:0002110	90.52	gold quality
right coronary artery	UBERON:0001625	89.37	gold quality
upper lobe of left lung	UBERON:0008952	89.36	gold quality
caecum	UBERON:0001153	88.76	gold quality
upper lobe of lung	UBERON:0008948	88.08	gold quality
sural nerve	UBERON:0015488	87.92	gold quality
bone marrow	UBERON:0002371	87.35	gold quality
pancreatic ductal cell	CL:0002079	87.29	gold quality
colonic epithelium	UBERON:0000397	86.61	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.53	gold quality
right lung	UBERON:0002167	85.13	gold quality
omental fat pad	UBERON:0010414	84.86	gold quality
peritoneum	UBERON:0002358	84.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.32	gold quality
bone element	UBERON:0001474	83.86	gold quality
small intestine	UBERON:0002108	83.32	gold quality
rectum	UBERON:0001052	83.26	gold quality
descending thoracic aorta	UBERON:0002345	83.04	gold quality
tonsil	UBERON:0002372	82.77	gold quality
apex of heart	UBERON:0002098	81.79	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	17.90
E-CURD-112	yes	16.50
E-ANND-3	yes	15.91
E-HCAD-10	yes	8.39
E-MTAB-9801	yes	6.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting CYTH4, 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-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3191-3P	99.45	63.94	356

Literature-anchored findings (GeneRIF, showing 2)

• This is the first evidence of a link between a primate-specific short tandem repeat of promoter of CYTH4 and a major psychiatric disorder in human (PMID:25240857)
• Novel alleles were detected at the long extreme of the GTTT-repeat, at 10- and 11-repeats, in the Schizophrenia cases and controls.Three genotypes consisting of the 11-repeat allele (i.e., 11/11, 10/11, and 7/11) were detected only in the Schizophrenia patients. The frequency of the 11-repeat allele was estimated at 0.02 and 0.006 in the Schizophrenia patients and controls, respectively (PMID:28723299)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyth4a	ENSDARG00000038011
danio_rerio	cyth4b	ENSDARG00000103984
mus_musculus	Cyth4	ENSMUSG00000018008
rattus_norvegicus	Cyth4	ENSRNOG00000007679
drosophila_melanogaster	siz	FBGN0026179
caenorhabditis_elegans		WBGENE00001743

Paralogs (15): CYTH3 (ENSG00000008256), PSD (ENSG00000059915), MON2 (ENSG00000061987), ARFGEF1 (ENSG00000066777), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), IQSEC2 (ENSG00000124313), PSD4 (ENSG00000125637), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

Cytohesin-4 — Q9UIA0 (reviewed: Q9UIA0)

Alternative names: PH, SEC7 and coiled-coil domain-containing protein 4

All UniProt accessions (5): Q9UIA0, B1AHH4, B1AHH5, B1AHH6, H0Y724

UniProt curated annotations — full annotation on UniProt →

Function. Promotes guanine-nucleotide exchange on ARF1 and ARF5. Promotes the activation of ARF factors through replacement of GDP with GTP.

Subcellular location. Cell membrane.

Tissue specificity. Expressed predominantly in peripheral blood leukocytes.

Domain organisation. Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate. Autoinhibited by its C-terminal basic region.

RefSeq proteins (2): NP_001304953, NP_037517* (*=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 (10 total): binding site 4, domain 2, chain 1, region of interest 1, coiled-coil region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIA0-F1	87.17	0.58

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 268–275; 279; 290; 300

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6811438	Intra-Golgi traffic

MSigDB gene sets: 185 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, BOYLAN_MULTIPLE_MYELOMA_D_DN, GNF2_MYD88, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, HOEBEKE_LYMPHOID_STEM_CELL_UP, RGAGGAARY_PU1_Q6, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, SHEN_SMARCA2_TARGETS_DN, PARENT_MTOR_SIGNALING_UP, chr22q13, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY

GO Biological Process (1): regulation of ARF protein signal transduction (GO:0032012)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (6): Golgi membrane (GO:0000139), cytosol (GO:0005829), plasma membrane (GO:0005886), centriolar satellite (GO:0034451), intercellular bridge (GO:0045171), membrane (GO:0016020)

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
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
membrane	1
cell periphery	1
centrosome	1

Protein interactions and networks

STRING

1332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYTH4	ARF1	P10947	842
CYTH4	ARF6	P26438	841
CYTH4	TRIM23	P36406	686
CYTH4	FRMD4A	Q9P2Q2	649
CYTH4	ARL4A	P40617	643
CYTH4	FRMD4B	Q9Y2L6	629
CYTH4	ARF5	P26437	613
CYTH4	PLEK2	Q9NYT0	604
CYTH4	TAMALIN	Q7Z6J2	593
CYTH4	RACK1	P25388	591
CYTH4	CEACAM3	P40198	585
CYTH4	CCDC120	Q96HB5	556
CYTH4	CEACAM8	P31997	548
CYTH4	RABIF	P47224	525
CYTH4	A0A2Q2T6B6	A0A2Q2T6B6	522

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CNKSR1	CYTH4	psi-mi:“MI:0915”(physical association)	0.670
CCDC120	CYTH4	psi-mi:“MI:0915”(physical association)	0.670
IPCEF1	CYTH4	psi-mi:“MI:0915”(physical association)	0.670
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
CYTH4	KIAA1328	psi-mi:“MI:0915”(physical association)	0.560
CYTH4	DCDC2	psi-mi:“MI:0915”(physical association)	0.560
CYTH4	CCDC40	psi-mi:“MI:0915”(physical association)	0.560
KIAA1328	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
PCM1	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
DCDC2	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CCDC40	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CBY2	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
KANK2	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
HOOK2	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
KRT16	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
KRT34	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
FOSB	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
USHBP1	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CCDC197	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CTAG1A	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CCDC6	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
PSMB1	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
	CYTH4	psi-mi:“MI:0915”(physical association)	0.560
CYTH4	TRAF7	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (51): CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), AMOTL2 (Two-hybrid), TRIM54 (Two-hybrid), KRT40 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Reconstituted Complex), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CYTH4 (Two-hybrid), CCDC6 (Two-hybrid)

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2724 predictions. Top by Δscore:

Variant	Effect	Δscore
22:37282586:CAGGT:C	donor_loss	1.0000
22:37282588:GGT:G	donor_loss	1.0000
22:37282589:G:C	donor_loss	1.0000
22:37282589:G:GG	donor_gain	1.0000
22:37282590:T:A	donor_loss	1.0000
22:37292616:TGTA:T	acceptor_loss	1.0000
22:37292617:GTA:G	acceptor_loss	1.0000
22:37292619:A:AC	acceptor_loss	1.0000
22:37292619:A:AG	acceptor_gain	1.0000
22:37292620:G:GG	acceptor_gain	1.0000
22:37292620:GA:G	acceptor_gain	1.0000
22:37292620:GAGC:G	acceptor_gain	1.0000
22:37292620:GAGCC:G	acceptor_gain	1.0000
22:37292700:CCAGG:C	donor_loss	1.0000
22:37292702:AG:A	donor_gain	1.0000
22:37292702:AGGTG:A	donor_loss	1.0000
22:37292703:GG:G	donor_gain	1.0000
22:37292704:G:C	donor_loss	1.0000
22:37292704:G:GG	donor_gain	1.0000
22:37293139:GC:G	donor_gain	1.0000
22:37295994:CACA:C	acceptor_loss	1.0000
22:37295995:ACAGC:A	acceptor_loss	1.0000
22:37295997:A:AG	acceptor_gain	1.0000
22:37295997:AGCC:A	acceptor_gain	1.0000
22:37295997:AGCCG:A	acceptor_gain	1.0000
22:37295998:G:GC	acceptor_gain	1.0000
22:37295998:GCC:G	acceptor_gain	1.0000
22:37295998:GCCG:G	acceptor_gain	1.0000
22:37295998:GCCGG:G	acceptor_gain	1.0000
22:37296063:AAGG:A	donor_loss	1.0000

AlphaMissense

2637 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:37311027:T:C	L283P	1.000
22:37311050:T:C	F291L	1.000
22:37311052:C:A	F291L	1.000
22:37311052:C:G	F291L	1.000
22:37311478:T:A	I303K	1.000
22:37312158:T:A	W366R	1.000
22:37312158:T:C	W366R	1.000
22:37297664:G:A	G112D	0.999
22:37299306:G:C	R145T	0.999
22:37299306:G:T	R145M	0.999
22:37300975:C:A	A168D	0.999
22:37303274:T:C	F190L	0.999
22:37303276:C:A	F190L	0.999
22:37303276:C:G	F190L	0.999
22:37303290:T:C	L195P	0.999
22:37303294:C:A	N196K	0.999
22:37303294:C:G	N196K	0.999
22:37303302:T:C	L199P	0.999
22:37309305:G:C	G264R	0.999
22:37309308:T:A	W265R	0.999
22:37309308:T:C	W265R	0.999
22:37309312:T:C	L266P	0.999
22:37309319:G:C	K268N	0.999
22:37309319:G:T	K268N	0.999
22:37311005:T:A	W276R	0.999
22:37311005:T:C	W276R	0.999
22:37311017:T:A	W280R	0.999
22:37311017:T:C	W280R	0.999
22:37311020:T:C	F281L	0.999
22:37311022:C:A	F281L	0.999

dbSNP variants (sampled 300 via entrez): RS1000099098 (22:37280948 A>G), RS1000163646 (22:37311794 A>C,G), RS1000265954 (22:37306969 G>A), RS1000313886 (22:37295196 C>A,G), RS1000326184 (22:37281001 G>A), RS1000383415 (22:37295747 G>A,C), RS1000506592 (22:37285536 G>A), RS1000632501 (22:37290484 G>C), RS1000728428 (22:37290730 G>A,C), RS1000765112 (22:37307576 A>C,G), RS1000915899 (22:37296368 T>C), RS1000952545 (22:37286383 C>G,T), RS1001109036 (22:37302110 G>A), RS1001168779 (22:37298368 G>A,T), RS1001231840 (22:37295703 C>T)

Disease associations

OMIM: gene MIM:606514 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002408_16	Response to methotrexate in juvenile idiopathic arthritis	9.000000e-06
GCST004779_1	Uterine fibroids	8.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	3
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	increases expression	1
abrine	increases expression	1
2,6-dichloro-(1,4)benzoquinone	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Amphotericin B	increases expression	1
Arsenic	increases expression	1
Cisplatin	increases expression	1
Curcumin	increases expression	1
Estradiol	increases expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	increases expression	1

Clinical trials (associated diseases)

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