IGFBP6

Summary

IGFBP6 (insulin like growth factor binding protein 6, HGNC:5475) is a protein-coding gene on chromosome 12q13.13, encoding Insulin-like growth factor-binding protein 6 (P24592). 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.

Enables identical protein binding activity and insulin-like growth factor II binding activity. Involved in cell migration and positive regulation of stress-activated MAPK cascade. Part of insulin-like growth factor binary complex. Implicated in obesity. Biomarker of breast cancer; in situ carcinoma; leiomyoma; and neovascular inflammatory vitreoretinopathy.

Source: NCBI Gene 3489 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• MANE Select transcript: NM_002178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5475
Approved symbol	IGFBP6
Name	insulin like growth factor binding protein 6
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167779
Ensembl biotype	protein_coding
OMIM	146735
Entrez	3489

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000301464, ENST00000548176, ENST00000548547, ENST00000549628, ENST00000650247, ENST00000858466

RefSeq mRNA: 1 — MANE Select: NM_002178 NM_002178

CCDS: CCDS8846

Canonical transcript exons

ENST00000301464 — 4 exons

Exon	Start	End
ENSE00001116916	53097667	53098051
ENSE00003491071	53101041	53101160
ENSE00003507094	53102045	53102340
ENSE00003511957	53100712	53100857

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 120.2564 / max 3916.2101, expressed in 1458 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125700	98.3799	1379
125699	21.5374	1236
125703	0.3390	231

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.81	gold quality
tibial nerve	UBERON:0001323	99.67	gold quality
mucosa of stomach	UBERON:0001199	99.63	gold quality
endocervix	UBERON:0000458	99.59	gold quality
left uterine tube	UBERON:0001303	99.57	gold quality
right coronary artery	UBERON:0001625	99.56	gold quality
thoracic aorta	UBERON:0001515	99.50	gold quality
ascending aorta	UBERON:0001496	99.49	gold quality
descending thoracic aorta	UBERON:0002345	99.49	gold quality
trigeminal ganglion	UBERON:0001675	99.47	gold quality
left coronary artery	UBERON:0001626	99.45	gold quality
coronary artery	UBERON:0001621	99.44	gold quality
synovial joint	UBERON:0002217	99.43	gold quality
tendon of biceps brachii	UBERON:0008188	99.40	gold quality
adenohypophysis	UBERON:0002196	99.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.31	gold quality
aorta	UBERON:0000947	99.27	gold quality
vena cava	UBERON:0004087	99.24	gold quality
stromal cell of endometrium	CL:0002255	99.19	gold quality
popliteal artery	UBERON:0002250	99.12	gold quality
tibial artery	UBERON:0007610	99.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.12	gold quality
lower esophagus	UBERON:0013473	99.06	gold quality
ectocervix	UBERON:0012249	99.02	gold quality
urethra	UBERON:0000057	99.00	gold quality
right ovary	UBERON:0002118	98.98	gold quality
tendon	UBERON:0000043	98.90	gold quality
dorsal root ganglion	UBERON:0000044	98.78	gold quality
left ovary	UBERON:0002119	98.70	gold quality
cauda epididymis	UBERON:0004360	98.64	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	6612.27
E-MTAB-6653	yes	5313.41
E-MTAB-8322	yes	5311.59
E-CURD-126	yes	3391.35
E-HCAD-38	yes	3099.51
E-GEOD-134144	yes	2767.45
E-GEOD-135922	yes	2487.08
E-CURD-114	yes	2292.53
E-HCAD-24	yes	1543.16
E-MTAB-9435	yes	451.91
E-MTAB-6701	yes	145.01
E-HCAD-1	yes	84.58
E-MTAB-10287	yes	67.68
E-HCAD-11	yes	41.31
E-HCAD-10	yes	40.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, EGR1, FOXQ1, GLI1, HNF4A, NKX3-1, TCF3, TCF4, TCF7L1, TCF7L2

miRNA regulators (miRDB)

5 targeting IGFBP6, 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-6736-3P	96.98	65.22	1342
HSA-MIR-1226-5P	96.50	65.28	643
HSA-MIR-6734-5P	95.70	65.56	950
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-4765	93.11	66.17	737

Literature-anchored findings (GeneRIF, showing 40)

• Inhibition of human osteoblast marker gene expression by retinoids is mediated in part by insulin-like growth factor binding protein-6. (PMID:11914024)
• determination of blood levels in adult patients with severe liver disease before and after orthotopic liver transplantation (PMID:12006706)
• may function as an antiproliferative molecule suppressing mitogenic effects of insulin-like growth factors on Malassez cells (PMID:12558805)
• CCI-779 acts additively with IGFBP-6 to reduce rhabdomyosarcoma growth both in vitro and in vivo. (PMID:14710364)
• C-domain of IGFBP-6 consists of a thyroglobulin type 1 fold comprising an alpha-helix followed by a loop, a three-stranded antiparallel beta-sheet incorporating a second loop, and a disulfide-bonded flexible third loop. (PMID:15308688)
• A close correlation exists between residues of the carboxyl-terminal domain of IGFBP6 undergoing conformational change in 15N NMR spectroscopy studies with those that disappeared or broadened upon insulin-like growth factor (IGF-II) binding. (PMID:15366928)
• The expression of certain IGFBP is significantly altered in renal cell carcinoma (PMID:15661050)
• The IGFBP-6 protein is synthesized as propeptides with a hydrophobic leader sequence, removal of which yields a mature protein composed of 3 recognizable domains of similar size. (PMID:15797461)
• transgenic human IGFBP-6 mice may be considered a new tool for studies of the involvement of the brain IGF system in metabolism control and obesity. (PMID:15889232)
• p38 MAPK is involved in IGFBP-6-induced IGF-independent rhabdomyosarcoma cell migration (PMID:17519236)
• Toxic effect of TCDD on osteogenesis through altering IGFBP6 gene expression in osteoblasts is reported. (PMID:17978469)
• IGFBP-6 is translocated to the nucleus with functional consequences, and different members of the IGFBP family have specific nuclear import mechanisms. (PMID:18039785)
• These studies provide evidence that overexpression of IGFBP-6 suppresses human and murine osteoblast differentiation, that IGFBP-6 and LMP-1 physically interact, and supports the conclusion that this interaction may be functionally relevant. (PMID:18395833)
• TCDD at low concentrations may have a negative effect on cell apoptosis and down-regulate gene expression of IGFBP-6 in SaOS-2 cells. (PMID:18724896)
• bexarotene increased the occupancy of the identified enhancer element in IGFBP-6 gene by RXRalpha, RARbeta, cJun, cFos, and p300 (PMID:18957410)
• Data show that an increase in JNK activation in the presence of NFkappaB inhibition significantly increased the expression of IGFBP6. (PMID:18982452)
• IGFBP-6 is the effector of tumor suppressor activity of SEMA3B. (PMID:18985860)
• These results indicate that IGFBP-6 promotes Rh30 rhabdomyosarcoma chemotaxis in an IGF-independent manner, and that MAPK signaling pathways and their cross-talk play an important role in this process. (PMID:20432455)
• Kininogen-1 and IGFBP-6 are expressed in serum and vitreous humor in proliferative vitreoretinopathy patients. (PMID:21054968)
• IGFBP-6 inhibits osteoblastic differentiation mediated by vitamin d3 by directly binding the vitamin d receptor and inhibiting its function (PMID:21458526)
• The authors conclude that during hepatitis B/C virus infection, O-beta-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression. (PMID:21548981)
• These results suggest that the expression of IGFBP-6 in vascular endothelial cells is up-regulated by hypoxia and IGFBP-6 inhibits angiogenesis in vitro and in vivo (PMID:21618524)
• When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited and apoptotic cell death was increased. (PMID:21820463)
• Hh pathway is aberrant activation in colorectal carcinoma cell line. Its inhibitor may be effectual agent for colorectal cancer chemoprevention. Gli1 maintained cell survival by binding promoter regions and facilitating transcription of IGFBP6 and Bcl-2. (PMID:21940310)
• IGFBP-6 acts as a inhibitory mediator of thyroid hormone effects in osteoblast differentiation (PMID:21997736)
• Review of the IGF system in physiology and disease with a focus on the regulation and actions of IGFBP-6, and its potential roles in cancer cells. (PMID:23126425)
• This is the first report to implicate IGFBP-6 as a suppressor of cellular proliferation and IGF-II as an inducer of cellular contractility in this connective tissue disease. (PMID:23623986)
• When the concentrations of IGFBP-6 or KNG1 were greater than 98.5 pg/ml or 88.5 ng/ml, respectively, they predicted the proliferative vitreoretinopathy prognosis. (PMID:23808406)
• Data indicate that IGFBP-6 binds to prohibitin-2 on the cell membrane, and knockdown of the latter abrogates IGFBP-6-induced migration. (PMID:24003225)
• Our results indicate that IGF2 and IGFBP6 appear to govern various regulatory feedback mechanisms in periodontal ligament cells (PMID:24182837)
• IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway (PMID:24379119)
• CCL-18 and IGFBP-6 were identified as new potential serum biomarkers for prostate cancer. (PMID:24747338)
• We found that IGFBP6 and SATB2 were significantly down-regulated in HIV-infected CEM*174 cells and 3 different cohorts of HIV/AIDS patients while their promoters were predominantly hyper-methylated compared with normal controls. (PMID:26039376)
• This study thus investigated the relationship between IGFs-related proteins in diabetic patients and the incidence of colorectal carcinoma. (PMID:26976474)
• Results suggest that insulin like growth factor binding protein 6 (IGFBP6) may be an independent prognostic biomarker for nasopharyngeal carcinoma (NPC). (PMID:27623076)
• IGFBP6 might be an important regulator and prognostic factor for glioma. (PMID:27650075)
• We identified a novel SNP variant, Chr12:g.53494591T>C. c.T430C (p.S144P) in the insulin-like growth factor binding protein-6 (IGFBP6) gene. This variant was shared by all affected family members, but not by unaffected members. The c.T430C (p.S144P) variant of IGFBP6 was identified as the likely causal variant associated with increased risk of familial disc degeneration in the studied pedigree. (PMID:28829625)
• These findings demonstrated that hMSCCMmediated neuroprotection was attributed to IGF1Rmediated signaling, potentiated via the inhibition of IGF2 by IGFBP6. The results of the present study provide insight into the mechanism by which hMSC administration may promote recovery from nerve injury. (PMID:29039467)
• IGFBP-6 could inhibit invasion and migration of colorectal carcinoma cells (PMID:29439316)
• A decrease of IGFBP6 expression can involve a decrease in the expression of N-cadherin and transcription factor Slug. (PMID:29577195)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	igfbp6a	ENSDARG00000070941
danio_rerio	igfbp6b	ENSDARG00000090833
mus_musculus	Igfbp6	ENSMUSG00000023046
rattus_norvegicus	Igfbp6	ENSRNOG00000010977

Paralogs (5): IGFBP2 (ENSG00000115457), IGFBP5 (ENSG00000115461), IGFBP4 (ENSG00000141753), IGFBP3 (ENSG00000146674), IGFBP1 (ENSG00000146678)

Protein

Protein identifiers

Insulin-like growth factor-binding protein 6 — P24592 (reviewed: P24592)

All UniProt accessions (4): A0A3B3IUE0, P24592, F8VVA5, F8VYK9

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. Activates the MAPK signaling pathway and induces cell migration.

Subunit / interactions. Interacts (via C-terminal domain) with PHB2.

Subcellular location. Secreted.

Post-translational modifications. O-linked glycans consist of hexose (probably Gal), N-acetylhexosamine (probably GalNAc) and sialic acid residues. O-glycosylated with core 1 or possibly core 8 glycans. O-glycosylated on one site only in the region AA 143-168 in cerebrospinal fluid.

RefSeq proteins (1): NP_002169* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR000867	IGFBP-like	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR022321	IGFBP_1-6_chordata	Family
IPR022326	IGFBP-6	Family
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily

Pfam: PF00086

UniProt features (42 total): disulfide bond 8, strand 6, glycosylation site 5, sequence conflict 5, sequence variant 4, turn 4, domain 2, helix 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1RMJ	SOLUTION NMR
2JM2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24592-F1	71.56	0.33

Functional residue map

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

Disulfide bonds (8): 29–32, 40–44, 57–63, 71–84, 78–104, 163–190, 201–212, 214–234

Glycosylation sites (5): 145, 146, 152, 126, 144

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 256 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, AREB6_01, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, MODULE_66, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_UP

GO Biological Process (7): signal transduction (GO:0007165), negative regulation of cell population proliferation (GO:0008285), cell migration (GO:0016477), positive regulation of stress-activated MAPK cascade (GO:0032874), positive regulation of MAPK cascade (GO:0043410), regulation of insulin-like growth factor receptor signaling pathway (GO:0043567), negative regulation of canonical Wnt signaling pathway (GO:0090090)

GO Molecular Function (8): fibronectin binding (GO:0001968), signaling receptor binding (GO:0005102), insulin-like growth factor I binding (GO:0031994), insulin-like growth factor II binding (GO:0031995), identical protein binding (GO:0042802), 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), insulin-like growth factor binary complex (GO:0042568)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
insulin-like growth factor binding	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell motility	1
regulation of stress-activated MAPK cascade	1
positive regulation of MAPK cascade	1
stress-activated MAPK cascade	1
positive regulation of stress-activated protein kinase signaling cascade	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of signal transduction	1
insulin-like growth factor receptor signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1
growth factor binding	1
cellular anatomical structure	1
insulin-like growth factor binding protein complex	1

Protein interactions and networks

STRING

998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGFBP6	IGF1	P01343	997
IGFBP6	IGF2	P01344	997
IGFBP6	IGFBP1	P08833	955
IGFBP6	SOAT2	O75908	837
IGFBP6	IGFALS	P35858	767
IGFBP6	INS	P01308	756
IGFBP6	IGF1R	P08069	740
IGFBP6	IGF2R	P11717	691
IGFBP6	IGFBP7	Q16270	678
IGFBP6	KRT2	P35908	660
IGFBP6	FZD8	Q9H461	544
IGFBP6	IGFBP2	P18065	527
IGFBP6	RARG	P13631	524
IGFBP6	TG	P01266	517
IGFBP6	IGFBP3	P17936	491

IntAct

111 interactions, top by confidence:

A	B	Type	Score
IGFBP6	RABGGTB	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	KRTAP5-7	psi-mi:“MI:0915”(physical association)	0.560
ALPP	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
MSGN1	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	EPDR1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	EFEMP1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	POU4F2	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	ANKRD11	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	SMCP	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
GET3	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	C1orf74	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	CCDC116	psi-mi:“MI:0915”(physical association)	0.560
GAS8	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	UBAC1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	NCALD	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	RANBP10	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
MBD3	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	PLEKHA7	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	AQP1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP6	CCDC28A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (55): FAM115C (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), CDK19 (Affinity Capture-MS), PSMG3 (Affinity Capture-MS), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid), IGFBP6 (Two-hybrid)

ESM2 similar proteins: A4IIA2, A5A8Y8, B3F211, P01186, P08833, P10769, P12843, P13384, P15473, P16042, P16229, P17936, P18065, P19336, P21743, P21744, P24591, P24592, P24593, P24594, P24787, P24853, P35455, P35572, P47876, P47877, P47878, P47879, P47880, P49705, P51693, P97466, Q03157, Q05717, Q05718, Q07079, Q13253, Q28985, Q29400, Q32L50

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

588 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53097785:G:GT	donor_gain	1.0000
12:53100699:A:AG	acceptor_gain	1.0000
12:53100700:T:G	acceptor_gain	1.0000
12:53100710:A:AG	acceptor_gain	1.0000
12:53100710:AGTT:A	acceptor_gain	1.0000
12:53100711:G:GG	acceptor_gain	1.0000
12:53100711:GT:G	acceptor_gain	1.0000
12:53100711:GTT:G	acceptor_gain	1.0000
12:53100711:GTTG:G	acceptor_gain	1.0000
12:53100711:GTTGC:G	acceptor_gain	1.0000
12:53100839:TGTCC:T	donor_gain	1.0000
12:53100854:GATG:G	donor_gain	1.0000
12:53100857:GGTG:G	donor_loss	1.0000
12:53100858:G:GG	donor_gain	1.0000
12:53101039:A:AG	acceptor_gain	1.0000
12:53101039:AG:A	acceptor_gain	1.0000
12:53101039:AGG:A	acceptor_gain	1.0000
12:53101040:G:GT	acceptor_gain	1.0000
12:53101040:GG:G	acceptor_gain	1.0000
12:53101040:GGG:G	acceptor_gain	1.0000
12:53101040:GGGC:G	acceptor_gain	1.0000
12:53101040:GGGCC:G	acceptor_gain	1.0000
12:53101157:GCAG:G	donor_gain	1.0000
12:53101158:CAGG:C	donor_loss	1.0000
12:53101160:GGT:G	donor_loss	1.0000
12:53101161:GTGAG:G	donor_loss	1.0000
12:53101162:T:G	donor_loss	1.0000
12:53099265:A:AG	acceptor_gain	0.9900
12:53099266:G:GG	acceptor_gain	0.9900
12:53100794:G:GT	donor_gain	0.9900

AlphaMissense

1517 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53101123:C:A	P188H	0.999
12:53101128:T:A	C190S	0.999
12:53101129:G:C	C190S	0.999
12:53102083:G:C	W213C	0.999
12:53102083:G:T	W213C	0.999
12:53102099:G:T	G219C	0.999
12:53097967:T:A	C84S	0.998
12:53097968:G:C	C84S	0.998
12:53101047:T:A	C163S	0.998
12:53101048:G:C	C163S	0.998
12:53101122:C:A	P188T	0.998
12:53101129:G:A	C190Y	0.998
12:53101129:G:T	C190F	0.998
12:53101140:G:T	G194C	0.998
12:53101146:T:G	Y196D	0.998
12:53101147:A:G	Y196C	0.998
12:53102045:T:A	C201S	0.998
12:53102046:G:C	C201S	0.998
12:53101048:G:A	C163Y	0.997
12:53101122:C:T	P188S	0.997
12:53101160:G:C	Q200H	0.997
12:53101160:G:T	Q200H	0.997
12:53102100:G:T	G219V	0.997
12:53101048:G:T	C163F	0.996
12:53101049:C:G	C163W	0.996
12:53101123:C:G	P188R	0.996
12:53101130:T:G	C190W	0.996
12:53098027:T:A	C104S	0.995
12:53098028:G:C	C104S	0.995
12:53101047:T:C	C163R	0.995

dbSNP variants (sampled 300 via entrez): RS1000948582 (12:53102506 C>T), RS1001104996 (12:53096682 C>A), RS1001124364 (12:53099771 T>C), RS1001740668 (12:53099486 A>G), RS1002056412 (12:53098050 T>A,C), RS1002358473 (12:53099309 C>G,T), RS1002474814 (12:53098879 G>A,C), RS1004819661 (12:53097589 A>AC), RS1004970619 (12:53099428 T>G), RS1005152424 (12:53096089 CT>C), RS1006611321 (12:53101391 T>C), RS1007751221 (12:53097619 G>A), RS1008167441 (12:53100272 G>A), RS1008227995 (12:53099818 TTAAG>T), RS10082746 (12:53100564 T>C)

Disease associations

OMIM: gene MIM:146735 | 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
GCST009144_5	Disease progression in age-related macular degeneration (adjusted for baseline)	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2139 (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
7.63	Ki	23.65	nM	CHEMBL292700
7.07	Ki	84.65	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	93355: The compound was tested for binding affinity against Insulin-like growth factor binding protein 6	ki	0.0237	uM
1-(3,4-dihydroxybenzoyl)-6,7-dihydroxy-2H-isoquinolin-3-one	93355: The compound was tested for binding affinity against Insulin-like growth factor binding protein 6	ki	0.0847	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression	4
Tretinoin	decreases expression, increases expression	4
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	3
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
nickel sulfate	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Arsenic	affects expression, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	increases expression, affects methylation	2
Cisplatin	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
cyclopamine	increases response to substance	1
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, increases expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
lead acetate	increases expression	1
pyrithione zinc	decreases expression	1
terbufos	decreases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	decreases expression, increases methylation	1
trimellitic anhydride	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
cupric chloride	decreases 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
CHEMBL700615	Binding	The compound was tested for binding affinity against Insulin-like growth factor binding protein 6	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.