IGFBP4

Summary

IGFBP4 (insulin like growth factor binding protein 4, HGNC:5473) is a protein-coding gene on chromosome 17q21.2, encoding Insulin-like growth factor-binding protein 4 (P22692). IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture.

This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors.

Source: NCBI Gene 3487 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 38 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001552

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5473
Approved symbol	IGFBP4
Name	insulin like growth factor binding protein 4
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	IBP4, BP-4, HT29-IGFBP, IGFBP-4
Ensembl gene	ENSG00000141753
Ensembl biotype	protein_coding
OMIM	146733
Entrez	3487

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000269593, ENST00000906679, ENST00000906680, ENST00000906681, ENST00000941634

RefSeq mRNA: 1 — MANE Select: NM_001552 NM_001552

CCDS: CCDS11367

Canonical transcript exons

ENST00000269593 — 4 exons

Exon	Start	End
ENSE00000950748	40452985	40453142
ENSE00001058066	40453928	40454062
ENSE00001231320	40456449	40457725
ENSE00001415258	40443450	40444084

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 403.3396 / max 8283.7023, expressed in 1613 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160748	403.3396	1613

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.82	gold quality
decidua	UBERON:0002450	99.72	gold quality
right ovary	UBERON:0002118	99.71	gold quality
left ovary	UBERON:0002119	99.65	gold quality
left uterine tube	UBERON:0001303	99.62	gold quality
right lobe of liver	UBERON:0001114	99.59	gold quality
endocervix	UBERON:0000458	99.57	gold quality
right lobe of thyroid gland	UBERON:0001119	99.57	gold quality
body of uterus	UBERON:0009853	99.57	gold quality
omental fat pad	UBERON:0010414	99.52	gold quality
peritoneum	UBERON:0002358	99.51	gold quality
smooth muscle tissue	UBERON:0001135	99.50	gold quality
gall bladder	UBERON:0002110	99.46	gold quality
left lobe of thyroid gland	UBERON:0001120	99.43	gold quality
pericardium	UBERON:0002407	99.43	gold quality
mucosa of stomach	UBERON:0001199	99.41	gold quality
myometrium	UBERON:0001296	99.38	gold quality
apex of heart	UBERON:0002098	99.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.37	gold quality
ectocervix	UBERON:0012249	99.34	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.33	gold quality
metanephros cortex	UBERON:0010533	99.31	gold quality
nerve	UBERON:0001021	99.30	gold quality
tibial nerve	UBERON:0001323	99.30	gold quality
right uterine tube	UBERON:0001302	99.28	gold quality
lower esophagus	UBERON:0013473	99.24	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.24	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.22	gold quality
coronary artery	UBERON:0001621	99.19	gold quality
left coronary artery	UBERON:0001626	99.19	gold quality

Single-cell (SCXA)

Detected in 35 experiment(s), a significant marker in 33.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	5367.33
E-GEOD-135922	yes	2974.29
E-MTAB-7051	yes	2880.69
E-CURD-126	yes	2552.09
E-HCAD-13	yes	2477.19
E-MTAB-6701	yes	2315.83
E-MTAB-10885	yes	1943.98
E-MTAB-9906	yes	1750.16
E-MTAB-8559	yes	1543.51
E-MTAB-9154	yes	1380.45
E-MTAB-8221	yes	1053.53
E-MTAB-9067	yes	1043.63
E-MTAB-10662	yes	1018.97
E-CURD-122	yes	657.69
E-GEOD-83139	yes	314.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ESR1, HMGA2, JUN, PGR, SOX9, SP1, SP3, TBP, WT1

miRNA regulators (miRDB)

70 targeting IGFBP4, 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-4533	100.00	69.48	2758
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785

Literature-anchored findings (GeneRIF, showing 40)

• enterocyte HT-29 cell differentiation correlates with an increase in IGFBP-4 levels (PMID:12163000)
• results are the first evidence of IGF-independent IGFBP-4 actions on granulosa cell steroidogenesis (PMID:12193384)
• role in sequestration of insulin-like growth factor-1 and consequent impairment of insulin-like growth factor-1 action in skeletal tissue (PMID:12733722)
• A novel SP3 binding site was identified in the promoter of IGFBP4. (PMID:14767471)
• IGFBP-4 proteolysis and local regulation of IGF availability may be altered in malignant ovarian epithelial cells (PMID:15146551)
• Data suggested that growth factor- and cytokine-mediated changes in IGFBP abundance regulate postnatal fibroblast cell. proliferation (PMID:15204833)
• The expression of certain IGFBP is significantly altered in renal cell carcinoma (PMID:15661050)
• IGFBP-4 is a novel dB-cAMP-induced anti-angiogenic and anti-tumorigenic mediator that may be a promising candidate for glioblastoma therapy. (PMID:16586492)
• Overexpression of IGFBP-4 in vivo has been reported to decrease the growth of prostate cancer and altered expression of IGFBP-4 in vivo in colon and other cancers needs to be explored as locally available IGFs appear to stimulate mitogenesis. (review) (PMID:16685432)
• The structures reveal the mechanisms of insulin-like growth factor (IGF) signaling regulation via insulin-like growth factor-binding proteins (IGFBP) binding. (PMID:16924115)
• local increased collagen synthesis was preceded by an elevation of local concentration of IGFBP-4, suggesting that IGFBP-4 may have a key role in the IGF-axis effect on the human collagen synthesis in vivo (PMID:16973813)
• High IGF-II, IGFBP-3, IGFBP-4, and low PAPP-A levels in FF at the time of oocyte retrieval suggest better oocyte maturation and early embryo development. (PMID:17070193)
• These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. (PMID:17071580)
• the IGF system may have a limited role in the pathogenesis of GCT with PAPP-A subserving a function other than IGFBP-4 proteolysis (PMID:17177834)
• Ratios between IGFBPs and IGF (insulin-like growth factors), different IGFBPs, sequential proteolytic cleavage of IGFBPs, and association of activating proteinases are key elements in the regulation of IGF receptor stimulation. (PMID:17312271)
• IGFBP-4 may have a role in increasing necrosis and apoptosis, but in decreasing mitosis (PMID:17824980)
• conclusion: decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma; data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma (PMID:19025658)
• IGFBP4, which can inhibit IGF action, also increased during in-vitro decidualization of cultured human ESCs. (PMID:19038974)
• Revealed is a dose-dependent stimulating effect of the IGFBP2 and IGFBP4 on the migration of CD34-/CD133+ hematopoietic stem and progenitor cells. (PMID:19956906)
• These findings suggest that the expression of IGFBP-4 in adenocarcinoma cells in vivo is downregulated by epigenetic silencing in association with tumor differentiation, resulting in disruption of the mechanism of IGFBP-4-mediated growth inhibition. (PMID:21166939)
• This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis. (PMID:21207373)
• circulating IGFBP-4 levels are not influenced by secondary hyperparathyroidism in vitamin D deficiency rickets (PMID:21274331)
• The resistance of VEGF-stimulated angiogenesis to IGFBP-4 inhibition appears to depend on sustained activation of p38 MAPK as blocking its activity restored the anti-angiogenic effects of IGFBP-4 on VEGF-induced blood vessel growth in vivo (PMID:22134921)
• This study demonistrated that IGFBP4 was significantly decreased in skeletal muscel in patient with amyotrophic lateral sclerosis. (PMID:22246875)
• IGF1 haplotypes are associated with genetic susceptibility to high myopia in Chinese adults, whereas IGFBP3 and IGFBP4 are unlikely to be important in the genetic predisposition to high myopia (PMID:22332214)
• role of IGFBP-4 in regulating IGF bioavailability and provide new clues for the prevention and treatment of FGR (Fetal growth restriction). (PMID:22689691)
• IGFBP-4 was by far the most predominant IGFBP by immunoassay (PMID:23079385)
• IGFBP-4 modulates the efficiency of estrogen-triggered activation of the Akt/PKB signaling pathway which has been associated with growth factor/ ERalpha cross-talks. (PMID:23499909)
• Epigenetic silencing of UCHL1 and IGFBP4 in giant cell tumors may be important for malignant transformation of the cells (PMID:23603559)
• these findings demonstrate an oncogenic property for IBP in promoting the metastatic potential of breast cancer cells. (PMID:23975422)
• PAPP-A and IGFBP-4 gene expression (microarray analysis) was significantly upregulated in IL-1beta- or TNF-alpha-exposed cells. (PMID:24060054)
• Despite the relation of CT-IGFBP4 to a more severe coronary artery disease, CT- and NT-IGFBP4, in contrast to our report based on total PAPP-A, failed to predict any long-term outcomes in patients with stable cardiovascular disease. (PMID:24201068)
• IGF-1/IGFbp4 signaling regulated the post-developmental adipose tissue expansion. (PMID:24778188)
• Data indicate co-localization of insulin-like growth factor binding proteins IGFBP-4, IGFBP-5 in the syncytiotrophoblast layer of first trimester placental villi as early as 5 weeks of gestational age. (PMID:25475528)
• PLasma IGFBP-4 levels are not acutely altered following myocardial infarction treated with heparin and percutaneous coronary intervention. (PMID:25489725)
• High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy. (PMID:26046968)
• The present study provides the first evidence that apoptosis inhibitor of macrophages binds to IGFBP2, 3 and 4. (PMID:26135353)
• Data show that co-transfection with cDNA encoding stanniocalcin-1 abrogates the proteolytic activity of pregnancy-associated plasma protein-A (PAPP-A) toward IGF-binding protein 4 (IGFBP-4). (PMID:26195635)
• Data show that insulin-like growth factor binding protein-4 (IGFBP-4) was significantly elevated in lupus nephritis, particularly those with renal pathology chronicity changes. (PMID:27019456)
• The authors also identified single-nucleotide polymorphisms in NRP2 and IGFBP4 loci that increase and reduce risk of lichen planus in hepatitis C virus-infected patients, respectively. (PMID:28065765)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Igfbp4	ENSMUSG00000017493
rattus_norvegicus	Igfbp4	ENSRNOG00000010635

Paralogs (5): IGFBP2 (ENSG00000115457), IGFBP5 (ENSG00000115461), IGFBP3 (ENSG00000146674), IGFBP1 (ENSG00000146678), IGFBP6 (ENSG00000167779)

Protein

Protein identifiers

Insulin-like growth factor-binding protein 4 — P22692 (reviewed: P22692)

All UniProt accessions (1): P22692

UniProt curated annotations — full annotation on UniProt →

Function. IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors.

Subunit / interactions. Binds IGF2 more than IGF1.

Subcellular location. Secreted.

Induction. By forskolin and N6,O2’dibutyryl adenosine 3’,5’-cyclic monophosphate, but not by 1,9 dideoxyforskolin.

Isoforms (2)

UniProt ID	Names	Canonical?
P22692-1	1	yes
P22692-2	2

RefSeq proteins (1): NP_001543* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR000867	IGFBP-like	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR017891	Insulin_GF-bd_Cys-rich_CS	Conserved_site
IPR022321	IGFBP_1-6_chordata	Family
IPR022327	IGFBP-4	Family
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily

Pfam: PF00086, PF00219

UniProt features (37 total): disulfide bond 10, strand 8, helix 6, sequence conflict 3, domain 2, signal peptide 1, chain 1, splice variant 1, sequence variant 1, turn 1, region of interest 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1WQJ	X-RAY DIFFRACTION	1.6
2DSR	X-RAY DIFFRACTION	2.1
2DSP	X-RAY DIFFRACTION	2.5
2DSQ	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22692-F1	77.46	0.36

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): 255

Disulfide bonds (10): 44–59, 67–80, 74–100, 131–138, 174–204, 215–226, 228–249, 27–53, 30–55, 38–56

Glycosylation sites (1): 125

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 409 (showing top): MODULE_52, MCLACHLAN_DENTAL_CARIES_UP, CMYB_01, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, IIZUKA_LIVER_CANCER_PROGRESSION_L1_G1_UP, MODULE_118, BROWNE_HCMV_INFECTION_48HR_DN, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN

GO Biological Process (10): MAPK cascade (GO:0000165), regulation of cell growth (GO:0001558), signal transduction (GO:0007165), regulation of glucose metabolic process (GO:0010906), positive regulation of MAPK cascade (GO:0043410), regulation of insulin-like growth factor receptor signaling pathway (GO:0043567), positive regulation of insulin-like growth factor receptor signaling pathway (GO:0043568), type B pancreatic cell proliferation (GO:0044342), negative regulation of canonical Wnt signaling pathway (GO:0090090), regulation of growth (GO:0040008)

GO Molecular Function (6): signaling receptor binding (GO:0005102), insulin-like growth factor I binding (GO:0031994), insulin-like growth factor II binding (GO:0031995), protein binding (GO:0005515), insulin-like growth factor binding (GO:0005520), growth factor binding (GO:0019838)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
insulin-like growth factor receptor signaling pathway	2
protein binding	2
insulin-like growth factor binding	2
intracellular signaling cassette	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of signal transduction	1
positive regulation of signal transduction	1
regulation of insulin-like growth factor receptor signaling pathway	1
epithelial cell proliferation	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
growth	1
regulation of biological process	1
binding	1
growth factor binding	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGFBP4	IGF1	P01343	997
IGFBP4	PAPPA	Q13219	960
IGFBP4	IGF2	P01344	937
IGFBP4	FZD8	Q9H461	831
IGFBP4	PRG2	P13727	819
IGFBP4	LRP6	O75581	793
IGFBP4	PAPPA2	Q9BXP8	720
IGFBP4	IGFALS	P35858	676
IGFBP4	INS	P01308	664
IGFBP4	IL6	P05231	630
IGFBP4	IL10	P22301	630
IGFBP4	IGF1R	P08069	604
IGFBP4	IGFBP7	Q16270	583
IGFBP4	TNF	P01375	570
IGFBP4	CRP	P02741	553

IntAct

71 interactions, top by confidence:

A	B	Type	Score
IGF1	IGFBP4	psi-mi:“MI:0407”(direct interaction)	0.760
IGFBP4	IGF1	psi-mi:“MI:0407”(direct interaction)	0.760
IGFBP1	IGF1	psi-mi:“MI:0407”(direct interaction)	0.620
DMWD	IGFBP4	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4		psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRN	IGFBP4	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	GSN	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	PMP22	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	WFS1	psi-mi:“MI:0915”(physical association)	0.560
BAG6	IGFBP4	psi-mi:“MI:0915”(physical association)	0.560
KLF11	IGFBP4	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	HTT	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	ATXN3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (46): RPL13 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), IMPDH2 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), IGFBP4 (Synthetic Lethality), IGFBP4 (Affinity Capture-MS), IGFBP4 (Proximity Label-MS), IGFBP4 (Proximity Label-MS), IGFBP4 (Reconstituted Complex), LONP2 (Affinity Capture-MS), NUDT12 (Affinity Capture-MS), CETN3 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), IGFBP4 (Affinity Capture-MS), NISCH (Affinity Capture-MS)

ESM2 similar proteins: B2RZ42, D4A6L0, E1BBQ2, J3QPP8, O02695, O62827, P01346, P01356, P06307, P06881, P09535, P12755, P12843, P15473, P16611, P17936, P20959, P22444, P22692, P24854, P47878, P49002, P49192, P49705, P53366, P55107, P55108, P56388, P80560, P97737, Q05716, Q08DX6, Q16568, Q26492, Q4RU86, Q58CS8, Q5T848, Q63475, Q68RJ9, Q6DVA0

Diamond homologs: A4IIA2, A5PKD8, B3F211, D3ZKF5, E1BJW1, P08833, P12843, P13384, P15473, P16611, P17936, P18065, P20959, P21743, P21744, P22692, P24591, P24592, P24593, P24594, P24853, P24854, P35572, P42642, P47876, P47877, P47878, P47879, P47880, P49705, Q05716, Q05717, Q05718, Q07079, Q16270, Q28893, Q28985, Q29400, Q5XHC5, Q61581

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	30
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
402159	NM_001552.3(IGFBP4):c.698C>T (p.Thr233Met)	Likely pathogenic

SpliceAI

430 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40444067:A:T	donor_gain	1.0000
17:40452976:T:TA	acceptor_gain	1.0000
17:40452981:ACAG:A	acceptor_loss	1.0000
17:40452982:CAGAC:C	acceptor_loss	1.0000
17:40452983:A:AG	acceptor_gain	1.0000
17:40452984:G:GA	acceptor_loss	1.0000
17:40452984:G:GG	acceptor_gain	1.0000
17:40453140:GTG:G	donor_gain	1.0000
17:40453143:G:GG	donor_gain	1.0000
17:40453143:GTA:G	donor_loss	1.0000
17:40453144:TAA:T	donor_loss	1.0000
17:40453926:A:AG	acceptor_gain	1.0000
17:40453927:G:GG	acceptor_gain	1.0000
17:40453927:GC:G	acceptor_gain	1.0000
17:40453927:GCC:G	acceptor_gain	1.0000
17:40453927:GCCCC:G	acceptor_gain	1.0000
17:40454059:GCAG:G	donor_gain	1.0000
17:40454060:CAGGT:C	donor_loss	1.0000
17:40454061:AGGT:A	donor_loss	1.0000
17:40454064:T:G	donor_loss	1.0000
17:40456444:GGCA:G	acceptor_loss	1.0000
17:40456445:GCA:G	acceptor_loss	1.0000
17:40456446:CA:C	acceptor_loss	1.0000
17:40456447:A:AC	acceptor_loss	1.0000
17:40456447:A:AG	acceptor_gain	1.0000
17:40456448:G:GC	acceptor_gain	1.0000
17:40456448:GT:G	acceptor_gain	1.0000
17:40456448:GTGTC:G	acceptor_gain	1.0000
17:40444083:TGGTA:T	donor_loss	0.9900
17:40444085:G:GG	donor_gain	0.9900

AlphaMissense

1675 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:40443935:G:A	C67Y	1.000
17:40443936:C:G	C67W	1.000
17:40443938:G:A	G68E	1.000
17:40443955:T:A	C74S	1.000
17:40443956:G:C	C74S	1.000
17:40443973:T:A	C80S	1.000
17:40443973:T:C	C80R	1.000
17:40443974:G:C	C80S	1.000
17:40443975:C:G	C80W	1.000
17:40444033:T:A	C100S	1.000
17:40444033:T:C	C100R	1.000
17:40444034:G:A	C100Y	1.000
17:40444034:G:C	C100S	1.000
17:40444035:C:G	C100W	1.000
17:40453940:T:A	C174S	1.000
17:40453940:T:C	C174R	1.000
17:40453941:G:A	C174Y	1.000
17:40453941:G:C	C174S	1.000
17:40453942:C:G	C174W	1.000
17:40454024:C:A	P202T	1.000
17:40454024:C:T	P202S	1.000
17:40454025:C:A	P202H	1.000
17:40454029:C:A	N203K	1.000
17:40454029:C:G	N203K	1.000
17:40454030:T:A	C204S	1.000
17:40454030:T:C	C204R	1.000
17:40454031:G:A	C204Y	1.000
17:40454031:G:C	C204S	1.000
17:40454031:G:T	C204F	1.000
17:40454032:C:G	C204W	1.000

dbSNP variants (sampled 300 via entrez): RS1000004900 (17:40444108 T>C,G), RS1000041195 (17:40445720 G>A), RS1000112456 (17:40444003 C>T), RS1000710890 (17:40445875 CT>C), RS1000983391 (17:40450422 C>T), RS1001165794 (17:40456879 C>A,G,T), RS1001177658 (17:40451922 C>G,T), RS1001284380 (17:40457157 G>A,T), RS1001313526 (17:40452215 C>T), RS1001807781 (17:40454340 C>T), RS1002016870 (17:40447009 G>C,T), RS1002059458 (17:40448276 A>G), RS1002081525 (17:40445674 G>A), RS1002112099 (17:40454755 C>A), RS1002120700 (17:40447054 C>T)

Disease associations

OMIM: gene MIM:146733 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001956_10	Height	5.000000e-12
GCST005434_31	Pancreatic cancer	1.000000e-06
GCST007235_7	Pancreatic ductal adenocarcinoma	7.000000e-06
GCST008839_26	Height	1.000000e-20

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2310 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.98	Ki	1.04	nM	CHEMBL292700
8.21	Ki	6.23	nM	CHEMBL130994

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-(3,4-dihydroxybenzoyl)-6,7-dihydroxyisoquinoline-3-carboxylic acid	93216: The compound was tested for binding affinity against Insulin-like growth factor binding protein 4	ki	0.0010	uM
1-(3,4-dihydroxybenzoyl)-6,7-dihydroxy-2H-isoquinolin-3-one	93217: The compound was tested for binding affinity against Insulin-like growth factor binding protein 4	ki	0.0062	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, affects expression, decreases expression, increases activity (+1 more)	14
Benzo(a)pyrene	increases expression, increases methylation, affects expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression, increases expression	4
bisphenol A	increases expression, decreases expression	3
afimoxifene	decreases reaction, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	3
Resveratrol	decreases reaction, increases degradation, affects cotreatment, decreases expression	3
Genistein	increases expression	3
Particulate Matter	increases expression, decreases expression, increases abundance	3
graphene oxide	increases expression	2
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression	2
Fulvestrant	decreases reaction, increases expression, decreases expression	2
Cadmium	increases expression, decreases reaction	2
Cisplatin	decreases response to substance, increases expression, decreases expression	2
Coumestrol	increases expression, affects reaction, affects cotreatment	2
Doxorubicin	increases expression, affects cotreatment, affects response to substance	2
Lipopolysaccharides	affects expression, affects response to substance, increases expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Aflatoxin B1	affects expression, increases expression	2
Paclitaxel	increases expression, affects cotreatment, affects response to substance	2
daidzein	increases expression	1
triphenyl phosphate	affects expression	1
N-methyladenosine	affects abundance, affects expression, affects methylation	1
salinomycin	decreases expression	1
decabromobiphenyl ether	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases expression, decreases reaction	1
trimellitic anhydride	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL698361	Binding	The compound was tested for binding affinity against Insulin-like growth factor binding protein 4	Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins. — J Med Chem

Clinical trials (associated diseases)

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