IPCEF1

Summary

IPCEF1 (interaction protein for cytohesin exchange factors 1, HGNC:21204) is a protein-coding gene on chromosome 6q25.2, encoding Interactor protein for cytohesin exchange factors 1 (Q8WWN9). Enhances the promotion of guanine-nucleotide exchange by PSCD2 on ARF6 in a concentration-dependent manner.

Predicted to enable peroxidase activity. Predicted to be involved in response to oxidative stress. Predicted to be located in cytoplasm and plasma membrane.

Source: NCBI Gene 26034 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 52 total
• MANE Select transcript: NM_001130700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21204
Approved symbol	IPCEF1
Name	interaction protein for cytohesin exchange factors 1
Location	6q25.2
Locus type	gene with protein product
Status	Approved
Aliases	PIP3-E, KIAA0403
Ensembl gene	ENSG00000074706
Ensembl biotype	protein_coding
OMIM	619948
Entrez	26034

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000265198, ENST00000367220, ENST00000422970, ENST00000470622, ENST00000484827, ENST00000517438, ENST00000518162, ENST00000519091, ENST00000519190, ENST00000519344, ENST00000519405, ENST00000520261, ENST00000522590, ENST00000890496, ENST00000890497, ENST00000890498, ENST00000890499, ENST00000890500, ENST00000890501, ENST00000967132

RefSeq mRNA: 7 — MANE Select: NM_001130700 NM_001130699, NM_001130700, NM_001394799, NM_001394800, NM_001394801, NM_001394802, NM_015553

CCDS: CCDS47509, CCDS5245

Canonical transcript exons

ENST00000367220 — 12 exons

Exon	Start	End
ENSE00000813820	154221257	154221328
ENSE00000813821	154223170	154223243
ENSE00001142670	154289713	154289756
ENSE00001443855	154265912	154265964
ENSE00001779259	154247449	154247488
ENSE00002124390	154356672	154356803
ENSE00002135765	154154496	154160040
ENSE00003534656	154246591	154246760
ENSE00003543856	154212770	154212855
ENSE00003620008	154199668	154200040
ENSE00003621870	154214218	154214276
ENSE00003662849	154167920	154168113

Expression profiles

Bgee: expression breadth ubiquitous, 230 present calls, max score 99.46.

FANTOM5 (CAGE): breadth broad, TPM avg 6.2680 / max 291.5564, expressed in 378 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76296	1.7549	206
76294	1.1301	173
76293	1.0263	169
76295	0.8151	179
76310	0.8044	172
76297	0.2968	112
76311	0.1269	46
76309	0.0948	41
76292	0.0570	35
76291	0.0551	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.28	gold quality
middle temporal gyrus	UBERON:0002771	98.61	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.42	gold quality
Brodmann (1909) area 10	UBERON:0013541	94.44	gold quality
superior frontal gyrus	UBERON:0002661	94.42	gold quality
orbitofrontal cortex	UBERON:0004167	94.16	gold quality
primary visual cortex	UBERON:0002436	93.57	gold quality
postcentral gyrus	UBERON:0002581	92.59	gold quality
parietal lobe	UBERON:0001872	92.55	gold quality
frontal pole	UBERON:0002795	92.32	gold quality
occipital lobe	UBERON:0002021	91.97	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.08	gold quality
prefrontal cortex	UBERON:0000451	89.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.90	gold quality
entorhinal cortex	UBERON:0002728	88.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.77	gold quality
frontal cortex	UBERON:0001870	88.62	gold quality
thyroid gland	UBERON:0002046	87.33	gold quality
neocortex	UBERON:0001950	87.32	gold quality
cerebellar vermis	UBERON:0004720	87.28	gold quality
paraflocculus	UBERON:0005351	87.08	gold quality
blood	UBERON:0000178	86.92	gold quality
left lobe of thyroid gland	UBERON:0001120	86.01	gold quality
leukocyte	CL:0000738	85.97	gold quality
monocyte	CL:0000576	85.94	gold quality
mononuclear cell	CL:0000842	85.89	gold quality
buccal mucosa cell	CL:0002336	85.76	gold quality
right lobe of thyroid gland	UBERON:0001119	85.33	gold quality
cerebral cortex	UBERON:0000956	84.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	19.03
E-ANND-3	yes	8.40
E-MTAB-9067	yes	4.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

163 targeting IPCEF1, 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-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 5)

• IPCEF1 increases the in vitro and in vivo stimulation of ARFGTP formation by cytohesin 2 (PMID:12920129)
• PTEN may down-regulate the expression of PIP3, and then down-regulate the expression of cyclin D1, which leads to the suppression of cell growth. (PMID:17067457)
• 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)
• CNK3 and IPCEF1 produce a single protein that is required for HGF dependent Arf6 activation and migration. (PMID:22085542)
• Circular RNA profiling reveals a potential role of hsa_circ_IPCEF1 in papillary thyroid carcinoma. (PMID:34165176)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ipcef1	ENSMUSG00000064065
rattus_norvegicus	Ipcef1	ENSRNOG00000018163
drosophila_melanogaster	cnk	FBGN0286070
caenorhabditis_elegans		WBGENE00000564

Paralogs (4): CNKSR1 (ENSG00000142675), CNKSR2 (ENSG00000149970), CNKSR3 (ENSG00000153721), SAMD3 (ENSG00000164483)

Protein

Protein identifiers

Interactor protein for cytohesin exchange factors 1 — Q8WWN9 (reviewed: Q8WWN9)

Alternative names: Phosphoinositide-binding protein PIP3-E

All UniProt accessions (6): Q8WWN9, A0A2Q2T6B6, E5RGB6, E5RGN6, E5RJQ7, E5RK08

UniProt curated annotations — full annotation on UniProt →

Function. Enhances the promotion of guanine-nucleotide exchange by PSCD2 on ARF6 in a concentration-dependent manner.

Subunit / interactions. Interacts with guanine-nucleotide exchange factors PSCD1, PSCD2, PSCD3 and PSCD4. Interacts (via C-terminus) with cytohesin-2 CYTH2.

Subcellular location. Cytoplasm. Cell membrane.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8WWN9-1	IPCEF1-1	yes
Q8WWN9-2	IPCEF1-2
G9CGD6-1	CNK3-IPCEF1-1, CNK3/IPCEF1 Long-1
G9CGD6-2	CNK3-IPCEF1-2, CNK3/IPCEF1 Long-2
G9CGD6-3	CNK3-IPCEF1-3, CNK3/IPCEF1 Short

RefSeq proteins (7): NP_001124171, NP_001124172, NP_001381728, NP_001381729, NP_001381730, NP_001381731, NP_056368 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR051566	CNKSR	Family

Pfam: PF00169

UniProt features (26 total): strand 8, region of interest 6, compositionally biased region 5, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5MR1	X-RAY DIFFRACTION	1.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWN9-F1	65.22	0.23

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 (1): 411

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 286 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, MODULE_255, MORF_ATRX, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_317, MORF_ESR1, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CAGCTG_AP4_Q5, BOYLAN_MULTIPLE_MYELOMA_D_DN, EVI1_05, chr6q25, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, SA_PTEN_PATHWAY, MORF_FANCG, GOBP_GAS_TRANSPORT

GO Biological Process (3): response to oxidative stress (GO:0006979), oxygen transport (GO:0015671), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (3): peroxidase activity (GO:0004601), oxygen carrier activity (GO:0005344), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
response to stress	1
gas transport	1
cellular detoxification	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
oxygen transport	1
oxygen binding	1
molecular carrier activity	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

31 interactions, top by confidence:

A	B	Type	Score
CYTH1	IPCEF1	psi-mi:“MI:0915”(physical association)	0.670
IPCEF1	CYTH2	psi-mi:“MI:0915”(physical association)	0.670
IPCEF1	CYTH4	psi-mi:“MI:0915”(physical association)	0.670
CYTH3	IPCEF1	psi-mi:“MI:0915”(physical association)	0.560
CEP70	IPCEF1	psi-mi:“MI:0915”(physical association)	0.560
USP7	IPCEF1	psi-mi:“MI:0407”(direct interaction)	0.440
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
WDR86	TXNDC9	psi-mi:“MI:0914”(association)	0.350
IPCEF1	CYTH3	psi-mi:“MI:0914”(association)	0.350
CYTH4	OFD1	psi-mi:“MI:0914”(association)	0.350
CYTH4	IPCEF1	psi-mi:“MI:0915”(physical association)	0.000
CYTH1	IPCEF1	psi-mi:“MI:0915”(physical association)	0.000
IPCEF1	CYTH2	psi-mi:“MI:0915”(physical association)	0.000
CYTH3	IPCEF1	psi-mi:“MI:0915”(physical association)	0.000
IPCEF1	CEP70	psi-mi:“MI:0915”(physical association)	0.000
IPCEF1	CYTH1	psi-mi:“MI:0915”(physical association)	0.000
CYTH2	IPCEF1	psi-mi:“MI:0915”(physical association)	0.000
IPCEF1	CYTH4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): CYTH1 (Affinity Capture-MS), CYTH2 (Affinity Capture-MS), CYTH3 (Affinity Capture-MS), TRIM11 (Affinity Capture-MS), IPCEF1 (Affinity Capture-MS), CYTH2 (Two-hybrid), IPCEF1 (Affinity Capture-Western), CYTH1 (Two-hybrid), CYTH3 (Two-hybrid), CYTH4 (Two-hybrid), IPCEF1 (Two-hybrid), CYTH1 (Reconstituted Complex), CYTH2 (Reconstituted Complex), CYTH3 (Reconstituted Complex), CYTH4 (Reconstituted Complex)

ESM2 similar proteins: A2AKB4, A4IFK0, A6QQV9, D4AB98, O62666, O62674, O62675, O62676, O62677, O62678, P49796, P52734, P59672, P78524, P97432, P98174, Q00IB7, Q0V8R5, Q32LQ1, Q3B7M3, Q501R9, Q53GL0, Q5BJM5, Q5DU31, Q5F3C8, Q5SYB0, Q6ZPF3, Q80TI1, Q80UZ0, Q80VL0, Q80XA6, Q80YS6, Q86XL3, Q8BL80, Q8BZI0, Q8C4S8, Q8IVF5, Q8K124, Q8N556, Q8NE31

Diamond homologs: B6RSP1, D3ZL52, G9CGD6, O08967, O43739, P54644, P60669, P97434, P97696, Q3UIL6, Q5DU31, Q6IQ23, Q6WCQ1, Q6ZNL6, Q7TQG1, Q80UZ0, Q80VL0, Q80YA9, Q86IV4, Q8BH49, Q8C4V1, Q8N264, Q8N4B1, Q8VC98, Q8WWN9, Q8WXI2, Q99KW3, Q9ERE6, Q9ERS5, Q9H4M7, Q9HAU0, Q9HB19, Q9Y2H5, Q9Z1T4, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2797 predictions. Top by Δscore:

Variant	Effect	Δscore
6:154160039:CACTG:C	acceptor_gain	1.0000
6:154160041:C:CC	acceptor_gain	1.0000
6:154160049:G:GC	acceptor_gain	1.0000
6:154168005:AACT:A	donor_gain	1.0000
6:154168109:CTCTT:C	acceptor_gain	1.0000
6:154168111:CTT:C	acceptor_gain	1.0000
6:154168117:T:TC	acceptor_gain	1.0000
6:154168118:T:C	acceptor_gain	1.0000
6:154168118:T:TC	acceptor_gain	1.0000
6:154200049:C:CT	acceptor_gain	1.0000
6:154200061:C:CT	acceptor_gain	1.0000
6:154200062:A:T	acceptor_gain	1.0000
6:154212764:ACAT:A	donor_loss	1.0000
6:154212765:CAT:C	donor_loss	1.0000
6:154212766:AT:A	donor_loss	1.0000
6:154212766:ATAC:A	donor_loss	1.0000
6:154212767:T:TG	donor_loss	1.0000
6:154212768:A:AC	donor_gain	1.0000
6:154212768:A:AG	donor_loss	1.0000
6:154212769:C:CC	donor_gain	1.0000
6:154212852:CATT:C	acceptor_gain	1.0000
6:154212853:ATTC:A	acceptor_loss	1.0000
6:154212854:TT:T	acceptor_gain	1.0000
6:154212855:TCT:T	acceptor_loss	1.0000
6:154212855:TCTA:T	acceptor_loss	1.0000
6:154212856:C:CC	acceptor_gain	1.0000
6:154212856:C:CG	acceptor_loss	1.0000
6:154212857:T:C	acceptor_loss	1.0000
6:154214213:CATA:C	donor_loss	1.0000
6:154214214:ATAC:A	donor_loss	1.0000

AlphaMissense

2886 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:154246650:A:G	W524R	1.000
6:154246650:A:T	W524R	1.000
6:154159965:A:G	W855R	0.999
6:154159965:A:T	W855R	0.999
6:154160024:A:G	L835P	0.999
6:154167942:C:G	R822P	0.999
6:154167954:A:G	L818P	0.999
6:154214275:A:G	W593R	0.999
6:154214275:A:T	W593R	0.999
6:154223233:G:T	A547D	0.999
6:154246605:A:C	Y539D	0.999
6:154246608:A:G	W538R	0.999
6:154246608:A:T	W538R	0.999
6:154246611:A:C	Y537D	0.999
6:154246613:A:G	L536P	0.999
6:154246691:A:G	L510P	0.999
6:154159963:C:A	W855C	0.998
6:154159963:C:G	W855C	0.998
6:154159964:C:G	W855S	0.998
6:154159974:A:C	Y852D	0.998
6:154167943:G:C	R822G	0.998
6:154167984:C:G	R808P	0.998
6:154168054:C:G	A785P	0.998
6:154168074:A:G	L778P	0.998
6:154221285:C:G	A583P	0.998
6:154221287:A:G	F582S	0.998
6:154223221:A:T	V551D	0.998
6:154223227:C:T	G549E	0.998
6:154246648:C:A	W524C	0.998
6:154246648:C:G	W524C	0.998

dbSNP variants (sampled 300 via entrez): RS1000001818 (6:154306654 A>C), RS1000002231 (6:154299737 T>C,G), RS1000053465 (6:154211737 A>G), RS1000057954 (6:154174672 C>A), RS1000066930 (6:154195694 A>C,G), RS1000075416 (6:154218393 G>A), RS1000090205 (6:154195540 G>C,T), RS1000101453 (6:154348177 A>G,T), RS1000101840 (6:154281901 G>A,C), RS1000109110 (6:154323190 T>A), RS1000110335 (6:154262026 A>T), RS1000114813 (6:154171637 A>T), RS1000142017 (6:154302992 C>T), RS1000156050 (6:154236486 C>G,T), RS1000158431 (6:154246488 A>G)

Disease associations

OMIM: gene MIM:619948 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002299_4	Chronic lymphocytic leukemia	2.000000e-10
GCST003832_11	Asthma (childhood onset)	8.000000e-06
GCST004146_35	Chronic lymphocytic leukemia	4.000000e-08
GCST007732_21	Allergic disease (asthma, hay fever or eczema)	5.000000e-07
GCST008403_4	Arterial stiffness index	7.000000e-06
GCST010576_3	Chronotype (sMEQ score)	8.000000e-07
GCST011956_23	Systemic lupus erythematosus	2.000000e-08
GCST90014325_30	Asthma	9.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004517	arterial stiffness measurement
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

10 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2281617	IPCEF1, OPRM1	3	1.00	1	amphetamine
rs2236256	IPCEF1, OPRM1	3	1.50	1	cocaine
rs2236257	IPCEF1, OPRM1		0.00	0
rs2236258	IPCEF1, OPRM1		0.00	0
rs2236259	IPCEF1, OPRM1		0.00	0
rs6902403	IPCEF1, OPRM1		0.00	0
rs9479779	IPCEF1, OPRM1		0.00	0
rs10485060	IPCEF1, OPRM1		0.00	0
rs1852629	IPCEF1, OPRM1		0.00	0
rs9322453	IPCEF1, OPRM1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
nickel sulfate	decreases expression	2
bisphenol S	increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation	2
Tobacco Smoke Pollution	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sulforaphane	increases expression	1
ochratoxin A	decreases methylation, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Am 580	decreases expression	1
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Atrazine	increases expression	1
Copper	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Eugenol	decreases expression	1
Glucose	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Nickel	increases expression	1
Nitrogen Dioxide	decreases expression	1
Ozone	increases expression, increases abundance	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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