INSIG2

Summary

INSIG2 (insulin induced gene 2, HGNC:20452) is a protein-coding gene on chromosome 2q14.1-q14.2, encoding Insulin-induced gene 2 protein (Q9Y5U4). Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR.

The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi.

Source: NCBI Gene 51141 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_016133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20452
Approved symbol	INSIG2
Name	insulin induced gene 2
Location	2q14.1-q14.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125629
Ensembl biotype	protein_coding
OMIM	608660
Entrez	51141

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000245787, ENST00000411929, ENST00000467223, ENST00000471186, ENST00000479999, ENST00000485520, ENST00000488995, ENST00000864770, ENST00000864771, ENST00000864772, ENST00000864773, ENST00000864774, ENST00000864775, ENST00000934788, ENST00000951469, ENST00000951470

RefSeq mRNA: 6 — MANE Select: NM_016133 NM_001321329, NM_001321330, NM_001321331, NM_001321332, NM_001321333, NM_016133

CCDS: CCDS2122

Canonical transcript exons

ENST00000245787 — 6 exons

Exon	Start	End
ENSE00001141042	118096419	118096800
ENSE00001942052	118108281	118110997
ENSE00003515354	118106737	118106903
ENSE00003588431	118107090	118107189
ENSE00003606845	118103197	118103321
ENSE00003842599	118088471	118088541

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 95.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5837 / max 215.3042, expressed in 1681 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22233	7.2173	1673
22236	0.3178	159
22234	0.0486	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	95.44	gold quality
right lobe of liver	UBERON:0001114	94.28	gold quality
body of pancreas	UBERON:0001150	94.23	gold quality
islet of Langerhans	UBERON:0000006	94.07	gold quality
tibia	UBERON:0000979	93.31	gold quality
tibial artery	UBERON:0007610	93.15	gold quality
popliteal artery	UBERON:0002250	93.14	gold quality
pancreas	UBERON:0001264	93.06	gold quality
aorta	UBERON:0000947	92.99	gold quality
left coronary artery	UBERON:0001626	92.95	gold quality
ascending aorta	UBERON:0001496	92.93	gold quality
thoracic aorta	UBERON:0001515	92.91	gold quality
cartilage tissue	UBERON:0002418	92.46	gold quality
descending thoracic aorta	UBERON:0002345	92.42	gold quality
coronary artery	UBERON:0001621	92.10	gold quality
right lung	UBERON:0002167	91.94	gold quality
body of stomach	UBERON:0001161	91.29	gold quality
skin of leg	UBERON:0001511	91.29	gold quality
skin of abdomen	UBERON:0001416	91.27	gold quality
upper lobe of left lung	UBERON:0008952	91.01	gold quality
liver	UBERON:0002107	90.97	gold quality
upper lobe of lung	UBERON:0008948	90.83	gold quality
spleen	UBERON:0002106	90.62	gold quality
zone of skin	UBERON:0000014	90.34	gold quality
stomach	UBERON:0000945	90.00	gold quality
left ovary	UBERON:0002119	89.79	gold quality
right ovary	UBERON:0002118	89.70	gold quality
gall bladder	UBERON:0002110	89.53	gold quality
decidua	UBERON:0002450	89.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELK4, NR1H2, NR1H3, VDR

miRNA regulators (miRDB)

101 targeting INSIG2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• Required for sterol-regulated transport of SREBPs from ER to Golgi. (PMID:12842885)
• degradation of ubiquitinated Insigs is controlled by serine residues flanking the sites of ubiquitination (PMID:16549805)
• These studies identify a aspartic acid residue that is crucial for the function of Insig1 and Insig2 proteins in regulating cholesterol homeostasis in mammalian cells. (PMID:16606821)
• INSIG-2 is a membrane bound oxysterol-binding protein with specificity for cholesterol derivatives that possess hydroxyl groups on the side chain. (PMID:17428920)
• The association of a SNP upstream of INSIG2 with body mass index is not reproduced in all cohorts. (PMID:17465681)
• The rs7566605 single-nucleotide polymorphism (SNP) was not related to plasma triglyceride levels. This suggests that, at the least, the true size of the effect on obesity of this SNP is likely to be considerably less than reported previously. (PMID:17471297)
• the variant upstream of INSIG2 is not a determinant of BMI in Indian population. (PMID:17489846)
• Children who were CC-homozygotes at SNP rs7566605 in the vicinity of INSIG2 lost less weight in this lifestyle intervention. (PMID:18003761)
• There is no association of the rs7566605 variant with overweight in Japanese people. (PMID:18070740)
• There is a lack of association between single-nucleotide polymorphism rs7566605 and being overweight among the Japanese (in the middle-aged and elderly population). (PMID:18223638)
• results do not support an association of the INSIG2 gene with the regulation of body weight or parameters related to lipoprotein metabolism (PMID:18239574)
• found no significant association of rs7566605 polymorphism with body mass index (BMI) and waist circumference among all participants (P=0.52), however in subjects from Shangai, the C/C genotype was associated with higher risk of BMI and obesity (PMID:18270535)
• INSIG2 is involved in adipocyte metabolism and body weight regulation. (PMID:18319320)
• Increased BMI in morbid obesity is associated with a combination of FTO and INSIG2 SNPs. (PMID:18347269)
• Insig2 is a novel colon cancer biomarker, and suggest, for the first time, a reasonable connection between Insig2 and Bax-mediated apoptosis through the mitochondrial pathway. (PMID:18464289)
• Polymorphism may be associated with obesity and body mass index in an Indian population. (PMID:18514965)
• it is suggested that the CC genotype of the INSIG2 upstream SNP, rs7566605, is a protective genetic factor against hypercholesterolaemia, when exposed to a high-fat diet. (PMID:18570692)
• rs7566605 in the upstream region of the INSIG2 gene was found to be associated with obesity, i.e., severe obesity, in Japanese. (PMID:18615239)
• INSIG2 polymorphisms play no apparent role in the development of common forms of obesity in the Danish population but may influence body mass index and physical activity. (PMID:18682847)
• common variants in FTO and INSIG2 are nominally associated with quantitative measures of obesity (PMID:18839134)
• The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. (PMID:18989534)
• Our results show that the INSIG2 rs7566605 polymorphism underlies variation in subcutaneous adiposity in young adult women and suppresses the positive effects of resistance training on men (PMID:19105843)
• The single nucleotide polymorphism rs7566605 near the INSIG2 gene does not influence body mass index and is not associated directly with coronary artery disease or myocardial infarction or indirectly through cardiovascular risk factors. (PMID:19197259)
• The rs7566605 INSIG2 gene polymorphism is not associated with obesity-related traits and lipids in the European Youth Heart Study. (PMID:19197262)
• children with the combination of the INSIG2 CC genotype and the FTO AA genotype showed the worst outcome in a lifestyle intervention, suggesting that the effects of INSIG2 and FTO aggravate each other. (PMID:19224890)
• INSIG2 rs7566605 variant is not associated Chinese childhood obesity in two independent cohorts. (PMID:19263810)
• INSIG2 SNPs are associated with obesity and glucose homeostasis traits in Hispanics (PMID:19360016)
• K121Q, rs7566605, and rs894160 are not major contributing factors for obesity for ENPP1, INSIG2 and PLIN (PMID:19399648)
• INSIG2 rs7566605 variant does not play a major role in determining obesity risk in a racially and ethnically diverse sample of 24,722 individuals from four cohorts (PMID:19523229)
• Studies define Insig-1 and Insig-2 as the minimal requirement for sterol-accelerated degradation of the membrane domain of reductase. (PMID:19638338)
• we suggest the possible involvement of INSIG2 with the plasma level of the total cholesterol in women (PMID:19772594)
• A total of 15.1% of participants were overweight or obese at age 16 y. No associations with INSIG2 were found. (PMID:20007308)
• this study suggests that sequence variants in INSIG2 likely influence the risk for obesity related traits (PMID:20028541)
• a role of INSIG2 sequence variation in the regulation of cholesterol metabolism. (PMID:20045156)
• Deletion analyses on 3 kb of 5’-flanking DNA of the INSIG2 gene revealed the functional importance of a 350-bp region upstream of the transcription start site. (PMID:20145255)
• This study was unable to replicate significant associations in patients of European ancestry and weight-gain induced by antipsychotics with single-nucleotide polymorphisms in Insulin Induced Gene 2. (PMID:20373477)
• While study did not confirm an association between rs7566605 and BMI in obese children in Sardinia, abnormalities of glucose metabolism and genotype, indicate that INSIG2 may be involved in glucose metabolism. (PMID:20645959)
• Results indicated that this INSIG2 polymorphism has no significant effect on body mass index and plasma lipids in the Czech Slavonic population. (PMID:20653998)
• These results suggest that INSIG2 genetic variants may have a more direct role in lipid and apolipoprotein B/lipoprotein metabolism than in obesity. (PMID:20858904)
• In single-marker-based analysis, the INSIG2 rs11123469-C homozygous genotype was found to be more frequent in patients with metabolic syndrome than those without metabolic syndrome. (PMID:20877301)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	insig2	ENSDARG00000113367
mus_musculus	Insig2	ENSMUSG00000003721
rattus_norvegicus	Insig2	ENSRNOG00000002478

Paralogs (1): INSIG1 (ENSG00000186480)

Protein

Protein identifiers

Insulin-induced gene 2 protein — Q9Y5U4 (reviewed: Q9Y5U4)

All UniProt accessions (2): Q9Y5U4, F8WCG8

UniProt curated annotations — full annotation on UniProt →

Function. Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139.

Subunit / interactions. Interacts with SCAP; interaction is direct and only takes place in the presence of sterols; it prevents interaction between SCAP and the coat protein complex II (COPII). Associates with the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via its interaction with SCAP and only takes place in the presence of sterols. Interacts with RNF139. Interacts with RNF145.

Subcellular location. Endoplasmic reticulum membrane.

Post-translational modifications. Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG2 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes. Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as adipose tissues, undifferentiated myoblasts and liver, leading to its degradation. In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization. Oxidized at Cys-215 in differentiated myotubes, preventing ubiquitination at the same site, and resulting in protein stabilization.

Domain organisation. Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4. The KxHxx motif mediates association with the coatomer complex.

Similarity. Belongs to the INSIG family.

RefSeq proteins (6): NP_001308258, NP_001308259, NP_001308260, NP_001308261, NP_001308262, NP_057217* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025929	INSIG_fam	Family

Pfam: PF07281

UniProt features (37 total): mutagenesis site 18, topological domain 7, transmembrane region 6, modified residue 2, chain 1, short sequence motif 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4J82	X-RAY DIFFRACTION	1.46
6M49	ELECTRON MICROSCOPY	3.7
7ETW	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5U4-F1	77.27	0.35

Functional residue map

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

Catalytic / active sites (1): 115 (required for the recognition of 25-hydroxycholesterol)

Post-translational modifications (3): 151, 215, 215

Mutagenesis-validated functional residues (18):

Position	Phenotype
39	decreased binding to 25-hydroxycholesterol, leading to decreased interaction with scap.
77	decreased binding to 25-hydroxycholesterol, leading to decreased interaction with scap.
100–102	does not affect degradation of the protein.
113	abolished interaction with scap even in the presence of 25-hydroxycholesterol.
114	does not affect interaction with scap.
115	decreased binding to 25-hydroxycholesterol and subsequent interaction with scap.
116	does not affect interaction with scap.
117	abolished interaction with scap even in the presence of 25-hydroxycholesterol.
120	abolished interaction with scap even in the presence of 25-hydroxycholesterol.
132	abolished interaction with scap without affecting binding to 25-hydroxycholesterol.
136	decreased binding to 25-hydroxycholesterol and subsequent interaction with scap.
145	abolished interaction with scap without affecting binding to 25-hydroxycholesterol.
149	loss of ability to suppress the cleavage of srebp2 and to accelerate the degradation of hmgcr. abolished interaction wit
151	abolished phosphorylation by pck1, does not affect oxysterol-binding, does not affect the interaction with scap.
151	phosphomimetic mutant, reduced binding to oxysterol.
200	decreased binding to 25-hydroxycholesterol, leading to decreased interaction with scap.
214	promotes ubiquitination by amfr/gp78, which does not take place normally.
215	prevents degradation because of impaired ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 248 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, FISCHER_G1_S_CELL_CYCLE, MORF_BRCA1, MORF_ATRX, MENSE_HYPOXIA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (22): triglyceride metabolic process (GO:0006641), cholesterol biosynthetic process (GO:0006695), negative regulation of steroid biosynthetic process (GO:0010894), cellular response to insulin stimulus (GO:0032869), SREBP signaling pathway (GO:0032933), SREBP-SCAP complex retention in endoplasmic reticulum (GO:0036316), inner ear morphogenesis (GO:0042472), middle ear morphogenesis (GO:0042474), negative regulation of fatty acid biosynthetic process (GO:0045717), roof of mouth development (GO:0060021), cranial suture morphogenesis (GO:0060363), response to fatty acid (GO:0070542), NLS-bearing protein import into nucleus (GO:0006607), lipid metabolic process (GO:0006629), response to sterol depletion (GO:0006991), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), sterol biosynthetic process (GO:0016126), response to insulin (GO:0032868), response to lipid (GO:0033993), positive regulation of cholesterol biosynthetic process (GO:0045542), protein maturation (GO:0051604)

GO Molecular Function (4): oxysterol binding (GO:0008142), protein sequestering activity (GO:0140311), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), SREBP-SCAP-Insig complex (GO:0032937), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of steroids	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
steroid biosynthetic process	2
negative regulation of lipid biosynthetic process	2
ear morphogenesis	2
embryonic morphogenesis	2
sterol metabolic process	2
binding	2
acylglycerol metabolic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
negative regulation of steroid metabolic process	1
regulation of steroid biosynthetic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
ER-nucleus signaling pathway	1
cellular response to sterol depletion	1
maintenance of protein localization in endoplasmic reticulum	1
cellular response to sterol	1
negative regulation of SREBP signaling pathway	1
inner ear development	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
anatomical structure development	1
craniofacial suture morphogenesis	1
response to lipid	1
response to oxygen-containing compound	1
protein import into nucleus	1
primary metabolic process	1
response to stress	1
lipid metabolic process	1
secondary alcohol metabolic process	1
response to peptide hormone	1
response to chemical	1
sterol binding	1
protein binding	1
molecular sequestering activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1410 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSIG2	SCAP	Q12770	992
INSIG2	HMGCR	P04035	983
INSIG2	AMFR	P26442	900
INSIG2	SREBF1	P36956	877
INSIG2	SREBF2	Q12772	865
INSIG2	RNF139	Q8WU17	780
INSIG2	GPR85	P60893	775
INSIG2	MLXIPL	Q9NP71	772
INSIG2	FABP2	P12104	725
INSIG2	RNF145	Q96MT1	639
INSIG2	MC4R	P32245	594
INSIG2	NR1D1	P20393	588
INSIG2	FTO	Q9C0B1	583
INSIG2	FABP4	P15090	579
INSIG2	CYP51A1	Q16850	559

IntAct

125 interactions, top by confidence:

A	B	Type	Score
COP1	SEC27	psi-mi:“MI:0915”(physical association)	0.930
INSIG2	RNF5	psi-mi:“MI:0915”(physical association)	0.720
RNF5	INSIG2	psi-mi:“MI:0915”(physical association)	0.720
TMEM237	INSIG2	psi-mi:“MI:0915”(physical association)	0.600
INSIG2	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
INSIG2		psi-mi:“MI:0915”(physical association)	0.560
INSIG2	AQP6	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	PVR	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	STIM1	psi-mi:“MI:0915”(physical association)	0.560
INSIG2	ATP6V0B	psi-mi:“MI:0915”(physical association)	0.560
BIK	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
SLC16A10	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
SCN3B	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
TMEM14B	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
CYBC1	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
TMX2	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
GPR152	INSIG2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (196): INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), RNF145 (Affinity Capture-Western), AMFR (Affinity Capture-Western), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid), INSIG2 (Two-hybrid)

ESM2 similar proteins: A0A067DFU5, A0A067E3D8, A0A1E1FFM9, A0A1Y0BRF5, A0A9Y1LNE1, A0A9Y1LQX3, A2AJQ3, A2ARJ3, A9RA88, B6HV37, B6JWP7, F4HW17, O48962, O59802, O64761, O74870, O94673, P0DXH1, P25338, P38312, P47111, P70245, Q06537, Q0V982, Q10255, Q12155, Q28GF5, Q3TUD9, Q4V7N7, Q54VP1, Q55E32, Q5F3W2, Q5F410, Q5R687, Q5R8N9, Q5U3Y7, Q60490, Q641M3, Q66HF2, Q6DCP8

Diamond homologs: A0JNC3, A9RA88, B0CMA4, O15503, Q08755, Q0V9G6, Q5F3W2, Q5R687, Q5U4Q2, Q5ZMT9, Q66J27, Q6DF80, Q6PQZ3, Q80UA9, Q8AV61, Q8BGI3, Q8CFA6, Q91WG1, Q9Y5U4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ELK4	“up-regulates quantity by expression”	INSIG2	“transcriptional regulation”
RNF139	“down-regulates quantity”	INSIG2	ubiquitination
AKT	“down-regulates quantity by repression”	INSIG2
AKT	“down-regulates activity”	INSIG2
INSIG2	“down-regulates activity”	SCAP	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1338 predictions. Top by Δscore:

Variant	Effect	Δscore
2:118107089:GAT:G	acceptor_gain	1.0000
2:118108279:A:AG	acceptor_gain	1.0000
2:118108280:G:GA	acceptor_gain	1.0000
2:118108280:GTAC:G	acceptor_gain	1.0000
2:118108367:G:GT	donor_gain	1.0000
2:118096490:T:G	donor_gain	0.9900
2:118096507:G:GT	donor_gain	0.9900
2:118096507:G:T	donor_gain	0.9900
2:118101264:G:GG	donor_gain	0.9900
2:118107088:A:AG	acceptor_gain	0.9900
2:118107089:G:GG	acceptor_gain	0.9900
2:118107089:GATAT:G	acceptor_gain	0.9900
2:118107124:T:A	acceptor_gain	0.9900
2:118107185:CAATG:C	donor_loss	0.9900
2:118107186:AATG:A	donor_loss	0.9900
2:118107187:ATGGT:A	donor_loss	0.9900
2:118107188:TGG:T	donor_loss	0.9900
2:118107190:G:A	donor_loss	0.9900
2:118107191:TAAG:T	donor_loss	0.9900
2:118108279:AGTAC:A	acceptor_gain	0.9900
2:118108280:GT:G	acceptor_gain	0.9900
2:118108280:GTA:G	acceptor_gain	0.9900
2:118108280:GTACG:G	acceptor_gain	0.9900
2:118103839:A:G	donor_gain	0.9800
2:118106775:ACT:A	acceptor_gain	0.9800
2:118107083:ATTCT:A	acceptor_loss	0.9800
2:118107085:TCTA:T	acceptor_loss	0.9800
2:118107086:CTA:C	acceptor_loss	0.9800
2:118107087:TA:T	acceptor_loss	0.9800
2:118107088:A:G	acceptor_loss	0.9800

AlphaMissense

1450 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:118096789:G:A	G78D	1.000
2:118103206:G:A	G85E	1.000
2:118103265:T:A	W105R	1.000
2:118103265:T:C	W105R	1.000
2:118103301:G:C	G117R	1.000
2:118103302:G:A	G117D	1.000
2:118106800:T:A	W145R	1.000
2:118106800:T:C	W145R	1.000
2:118107124:T:A	W191R	1.000
2:118107124:T:C	W191R	1.000
2:118096671:G:A	G39R	0.999
2:118096671:G:C	G39R	0.999
2:118096672:G:A	G39E	0.999
2:118096770:T:A	W72R	0.999
2:118096770:T:C	W72R	0.999
2:118103205:G:A	G85R	0.999
2:118103205:G:C	G85R	0.999
2:118103205:G:T	G85W	0.999
2:118103267:G:C	W105C	0.999
2:118103267:G:T	W105C	0.999
2:118103283:T:C	C111R	0.999
2:118103290:C:A	A113E	0.999
2:118103295:T:C	F115L	0.999
2:118103297:T:A	F115L	0.999
2:118103297:T:G	F115L	0.999
2:118103299:T:A	V116D	0.999
2:118103305:T:A	I118K	0.999
2:118103309:T:A	N119K	0.999
2:118103309:T:G	N119K	0.999
2:118103313:G:C	A121P	0.999

dbSNP variants (sampled 300 via entrez): RS1000231634 (2:118097427 T>C), RS1000286775 (2:118104228 G>A), RS1000527112 (2:118099208 C>T), RS1000546304 (2:118108132 A>C,G), RS1000581686 (2:118105609 A>G), RS1000592018 (2:118092273 TAAAG>T), RS1000604884 (2:118097797 G>A,C), RS1000612892 (2:118105384 A>C,T), RS1000681284 (2:118087600 T>C), RS1000751188 (2:118087287 A>G), RS1000970936 (2:118098886 G>A,C), RS1001002134 (2:118094851 G>T), RS1001616537 (2:118102350 A>G), RS1001622886 (2:118110658 T>C), RS1001695028 (2:118110279 C>G)

Disease associations

OMIM: gene MIM:608660 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001482_28	Lumbar spine bone mineral density	1.000000e-10
GCST002221_19	Cholesterol, total	6.000000e-09
GCST002222_30	LDL cholesterol	2.000000e-12
GCST003824_1	Depression in response to interferon-based therapy in chronic hepatitis C	2.000000e-06
GCST003996_19	Monobrow	8.000000e-10
GCST004863_58	Mosquito bite size	2.000000e-07
GCST006288_268	Heel bone mineral density	3.000000e-09
GCST006288_576	Heel bone mineral density	5.000000e-10
GCST006612_29	LDL cholesterol	2.000000e-14
GCST006614_95	Total cholesterol levels	4.000000e-10
GCST006979_22	Heel bone mineral density	5.000000e-12
GCST006979_23	Heel bone mineral density	2.000000e-24
GCST008077_17	LDL cholesterol levels	1.000000e-09
GCST008077_66	LDL cholesterol levels	2.000000e-09
GCST008078_113	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-12
GCST008078_20	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-12
GCST008079_149	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-16
GCST008079_16	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-15
GCST008086_43	LDL cholesterol levels in current drinkers	1.000000e-09
GCST008086_62	LDL cholesterol levels in current drinkers	5.000000e-10
GCST010204_76	Low density lipoprotein cholesterol levels	7.000000e-22
GCST010243_202	Apolipoprotein B levels	3.000000e-23
GCST010245_134	LDL cholesterol levels	1.000000e-23
GCST011347_17	Low density lipoprotein cholesterol levels	1.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007006	depressive symptom measurement
EFO:0007859	response to interferon
EFO:0007906	synophrys measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009270	heel bone mineral density
EFO:0004329	alcohol drinking
EFO:0004615	apolipoprotein B measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17587100	Toxicity	3	antipsychotics	Schizophrenia

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7566605	INSIG2		0.00	0
rs10490624	INSIG2		0.00	0
rs11123469	INSIG2		0.00	0
rs17047764	INSIG2		0.00	0
rs17587100	INSIG2	3	0.00	1	antipsychotics

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, affects cotreatment, decreases expression	4
Cyclosporine	increases expression, decreases expression	4
methylmercuric chloride	decreases expression	3
Oxygen	decreases reaction, increases expression	3
sodium arsenite	affects expression, decreases expression, increases abundance	2
Arsenic	decreases expression, increases abundance, affects methylation	2
Calcitriol	affects cotreatment, increases expression	2
Dexamethasone	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects expression, decreases methylation, increases expression	2
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
trichostatin A	affects expression	1
methylparaben	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
zinc chloride	decreases reaction, increases expression	1
cobaltous chloride	increases expression, decreases reaction	1
linalool	increases expression	1
nickel sulfate	increases expression	1
resorcinol	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
vandetanib	increases expression	1
abrine	decreases expression	1
archazolid B	increases expression	1
Rosiglitazone	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7PC	SRD-14/pInsig-2	Transformed cell line	Female
CVCL_B7PF	SRD-15/pInsig-2	Transformed cell line	Female

Clinical trials (associated diseases)

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