INSIG1

Summary

INSIG1 (insulin induced gene 1, HGNC:6083) is a protein-coding gene on chromosome 7q36.3, encoding Insulin-induced gene 1 protein (O15503). Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR.

This gene encodes an endoplasmic reticulum membrane protein that regulates cholesterol metabolism, lipogenesis, and glucose homeostasis. The encoded protein has six transmembrane helices which contain an effector protein binding site. It binds the sterol-sensing domains of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and is essential for the sterol-mediated trafficking of these two proteins. It promotes the endoplasmic reticulum retention of SCAP and the ubiquitin-mediated degradation of HMG-CoA reductase. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3638 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 40 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005542

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6083
Approved symbol	INSIG1
Name	insulin induced gene 1
Location	7q36.3
Locus type	gene with protein product
Status	Approved
Aliases	CL-6, MGC1405
Ensembl gene	ENSG00000186480
Ensembl biotype	protein_coding
OMIM	602055
Entrez	3638

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000340368, ENST00000342407, ENST00000344756, ENST00000425172, ENST00000468307, ENST00000476756, ENST00000885533, ENST00000885534, ENST00000885535, ENST00000885536, ENST00000885537, ENST00000885538, ENST00000885539

RefSeq mRNA: 8 — MANE Select: NM_005542 NM_001346590, NM_001346591, NM_001346592, NM_001346593, NM_001346594, NM_005542, NM_198336, NM_198337

CCDS: CCDS5938, CCDS5939, CCDS94240

Canonical transcript exons

ENST00000340368 — 6 exons

Exon	Start	End
ENSE00001339421	155302251	155302417
ENSE00001339425	155301566	155301690
ENSE00001368663	155298259	155298697
ENSE00001902607	155308241	155310235
ENSE00003584283	155302747	155302846
ENSE00003849590	155297878	155297959

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 113.9242 / max 3231.9547, expressed in 1818 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82217	112.6834	1816
82220	0.6054	324
82218	0.3633	169
82219	0.2720	132

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	99.12	gold quality
right lobe of liver	UBERON:0001114	98.65	gold quality
liver	UBERON:0002107	98.41	gold quality
upper leg skin	UBERON:0004262	97.68	gold quality
adrenal tissue	UBERON:0018303	97.40	gold quality
choroid plexus epithelium	UBERON:0003911	97.32	gold quality
superior vestibular nucleus	UBERON:0007227	97.07	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.94	gold quality
pigmented layer of retina	UBERON:0001782	96.90	gold quality
islet of Langerhans	UBERON:0000006	96.86	gold quality
secondary oocyte	CL:0000655	96.70	gold quality
tibia	UBERON:0000979	96.54	gold quality
oocyte	CL:0000023	96.51	gold quality
ventricular zone	UBERON:0003053	96.41	gold quality
endothelial cell	CL:0000115	96.40	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.33	gold quality
ganglionic eminence	UBERON:0004023	96.32	gold quality
medulla oblongata	UBERON:0001896	96.27	gold quality
inferior olivary complex	UBERON:0002127	96.15	gold quality
vena cava	UBERON:0004087	96.12	gold quality
pons	UBERON:0000988	96.05	gold quality
dorsal root ganglion	UBERON:0000044	95.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.72	gold quality
pancreas	UBERON:0001264	95.65	gold quality
jejunal mucosa	UBERON:0000399	95.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.55	gold quality
spinal cord	UBERON:0002240	95.44	gold quality
substantia nigra pars compacta	UBERON:0001965	95.36	gold quality
parotid gland	UBERON:0001831	95.25	gold quality
trigeminal ganglion	UBERON:0001675	95.10	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	13.96
E-MTAB-9388	yes	7.73
E-MTAB-2983	no	739.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, PPARD, PPARG, SREBF1, SREBF2

miRNA regulators (miRDB)

111 targeting INSIG1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
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 37)

• INSIG1 and p41 Arp2/3 complex (p41-Arc)reduced expression might be involved in gastric cancer development or progression (PMID:12115587)
• INSIG-1 plays a role in regulating cholesterol concentration in human cells (PMID:12242342)
• Data show that Insig-1 appears to play an essential role in the sterol-mediated trafficking of two proteins with sterol-sensing domains, HMG CoA reductase and SCAP. (PMID:12535518)
• insig-1 expression restricts lipogenesis in mature adipocytes and blocks differentiation in preadipocytes (PMID:12869692)
• data indicate that short segments at the N and C termini of insulin induced gene 1(Insig-1) face the cytosol with most of the protein buried within the membrane, forming six transmembrane segments (PMID:14660594)
• nSREBPs are essential for high levels of lipid synthesis in the liver and indicate that Insig’s modulate nSREBP levels by binding and retaining SCAP in the ER. (PMID:15085196)
• Insig-1 has a role in feedback control of lipid synthesis in cultured cells (PMID:15247248)
• Insig-1 has a role in activation of sterol regulatory element-binding protein induced by cellular stress (PMID:15304479)
• Insig is required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro (PMID:15899885)
• Results identify gp78 as the E3 that initiates sterol-accelerated degradation of reductase, and Insig-1 as a bridge between gp78/VCP and the reductase substrate. (PMID:16168377)
• Under conditions of mild steroid depletion, the failure to ubiquinate Insig-1 causes a delay in release of the Scap/sterol regulatory element binding protein-2, but it does not abolish it. (PMID:16399501)
• 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-1 sterol-regulated degradation is mediated by the membrane-bound ubiquitin ligase gp78 (PMID:17043353)
• Population studies demonstrate that INSIG1 plays a role in glucose homeostasis. (PMID:17106696)
• Activation of CAR and PXR in mouse liver results in activation of Insig-1 along with reduced protein levels of the active form of sterol regulatory element binding protein 1 (Srebp-1). (PMID:18187584)
• Unsaturated fatty acid-mediated stabilization of Insig-1 enhances the ability of sterols to inhibit proteolytic activation of SREBP-1, which activates transcription of genes involved in fatty acid synthesis (PMID:18835813)
• The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. (PMID:18989534)
• Studies define Insig-1 and Insig-2 as the minimal requirement for sterol-accelerated degradation of the membrane domain of reductase. (PMID:19638338)
• These data suggest that p97 recruits proteasomes to polytopic ER proteins, such as Insig-1, even before they are extracted from membranes. (PMID:19815544)
• From genetic association studies, SNPs in INSIG1 (including the promoter region) influence hypertriglyceridemia. (PMID:19965593)
• Common variation in INSIG1 is unlikely to have a major effect on risk of type 2 diabetes risk in white Europeans. (PMID:20444954)
• No significant associations were found between polymorphisms of INSIG1 gene and metabolic syndrome; however, INSIG1 and INSIG2 interactions were found in the significant 3-locus and 4-locus gene-gene interaction models. (PMID:20877301)
• Data show the essential role of PPARgamma and PPARgamma coactivator 1alpha (PGC-1alpha) in up-regulating Insig-1/2 expression, defining a mechanistic pathway triggered by CD36, and leading to cholesterol depletion in hepatocytes. (PMID:24371122)
• Our results indicated that the dysregulation of INSIG1 and SREBF1 caused by ART were observed not only in the fetus but also in the placenta, primarily in the ICSI group (PMID:24484994)
• identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect. (PMID:25028659)
• INSIG1 variation may contribute to statin-induced changes in plasma triglycerides in a sex-specific manner. (PMID:26927283)
• Our findings suggest that miR-92a may affect cholesterol metabolism by repressing insig1, resulting in raised intracellular cholesterol levels and Golgi volume and hence enhanced protein secretion. (PMID:28146316)
• argue that precursor miR-122 molecules modulate polyadenylation site usage in Insig1 mRNAs, resulting in down-regulation of Insig1 protein abundance (PMID:28928276)
• Knock down of FADS1 did not significantly change cholesterol efflux (p=0.70), but knockdown of INSIG1 and LDLR resulted in highly significant reduction of the efflux to HDL (67% and 75% of control, respectively, p<0.001). (PMID:30118702)
• INSIG1 functions as a sentinel responsive to HIV-1 production and inhibits HIV-1 replication by degrading Gag, a process occurring at intracellular membrane sites such as the endoplasmic reticulum and endosomes where both INSIG1 and Gag may be located. (PMID:30563842)
• Investigation of the association between obesity and insulin-induced gene 1 polymorphism at 7q36.3 region in Uygur population in Xinjiang, China. (PMID:31658356)
• the gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis; findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of hepatocellular carcinoma (PMID:32322062)
• Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression. (PMID:33722690)
• The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity. (PMID:34198853)
• Insulin-induced genes INSIG1 and INSIG2 mediate oxysterol-dependent activation of the PERK-eIF2alpha-ATF4 axis. (PMID:34298014)
• A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer. (PMID:37087475)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	insig1	ENSDARG00000010658
mus_musculus	Insig1	ENSMUSG00000045294
rattus_norvegicus	Insig1	ENSRNOG00000006859
rattus_norvegicus	LOC120102490	ENSRNOG00000027445

Paralogs (1): INSIG2 (ENSG00000125629)

Protein

Protein identifiers

Insulin-induced gene 1 protein — O15503 (reviewed: O15503)

All UniProt accessions (4): C9JSG8, O15503, F5H6P3, H7C5L3

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 25-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 INSIG1 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 ligases AMFR/gp78 and/or RNF139. Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78.

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. Interaction with SCAP is mutually exclusive with PAQR3. Interacts with HMGCR (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at the ER membrane for its ubiquitination and degradation by the sterol-mediated ERAD pathway. Interacts with SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and subsequent ubiquitination of SOAT2/ACAT2. Interacts with RNF139. Interacts with RNF145.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in all tissues tested with highest expression in the liver.

Post-translational modifications. Phosphorylation at Ser-207 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG1 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes. Ubiquitinated by AMFR/gp78 in response to sterol deprivation, leading to its degradation: when the SCAP-SREBP complex becomes dissociated from INSIG1, INSIG1 is then ubiquitinated and degraded in proteasomes. Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex. Ubiquitinated by RNF139.

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

Induction. By insulin. Expressed at high levels when nuclear SREBP levels are high as a result of sterol deprivation.

Similarity. Belongs to the INSIG family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15503-1	1	yes
O15503-2	2

RefSeq proteins (8): NP_001333519, NP_001333520, NP_001333521, NP_001333522, NP_001333523, NP_005533, NP_938150, NP_938151 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025929	INSIG_fam	Family

Pfam: PF07281

UniProt features (32 total): topological domain 7, transmembrane region 6, mutagenesis site 5, sequence conflict 3, cross-link 2, splice variant 2, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, site 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4J81	X-RAY DIFFRACTION	1.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15503-F1	68.54	0.26

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): 171 (required for the recognition of 25-hydroxycholesterol)

Post-translational modifications (3): 207, 156, 158

Mutagenesis-validated functional residues (5):

Position	Phenotype
156	loss of ubiquitination and degradation.
158	loss of ubiquitination and degradation.
205	loss of ability to suppress the cleavage of srebp2 and to accelerate the degradation of hmgcr.
207	abolished phosphorylation by pck1, does not affect oxysterol-binding, does not affect the interaction with scap.
207	phosphomimetic mutant, reduced binding to oxysterol.

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: 479 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, TSUNODA_CISPLATIN_RESISTANCE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_STEROL_HOMEOSTASIS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_VESICLE_ORGANIZATION, MENSE_HYPOXIA_UP, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS

GO Biological Process (25): triglyceride metabolic process (GO:0006641), cholesterol biosynthetic process (GO:0006695), cellular response to insulin stimulus (GO:0032869), SREBP signaling pathway (GO:0032933), cellular response to sterol (GO:0036315), SREBP-SCAP complex retention in endoplasmic reticulum (GO:0036316), inner ear morphogenesis (GO:0042472), middle ear morphogenesis (GO:0042474), cholesterol homeostasis (GO:0042632), negative regulation of cholesterol biosynthetic process (GO:0045541), negative regulation of fat cell differentiation (GO:0045599), negative regulation of fatty acid biosynthetic process (GO:0045717), roof of mouth development (GO:0060021), cranial suture morphogenesis (GO:0060363), negative regulation of protein exit from endoplasmic reticulum (GO:0070862), negative regulation of cargo loading into COPII-coated vesicle (GO:1901303), 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), negative regulation of steroid biosynthetic process (GO:0010894), sterol biosynthetic process (GO:0016126), 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
ear morphogenesis	2
embryonic morphogenesis	2
binding	2
acylglycerol metabolic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol 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
response to sterol	1
cellular response to lipid	1
cellular response to oxygen-containing compound	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
sterol homeostasis	1
cholesterol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
negative regulation of cholesterol metabolic process	1
negative regulation of sterol biosynthetic process	1
negative regulation of alcohol biosynthetic process	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
anatomical structure development	1
craniofacial suture morphogenesis	1
protein exit from endoplasmic reticulum	1
regulation of protein exit from endoplasmic reticulum	1
negative regulation of intracellular protein transport	1
negative regulation of intracellular transport	1
COPII-coated vesicle cargo loading	1
regulation of cargo loading into COPII-coated vesicle	1
protein import into nucleus	1

Protein interactions and networks

STRING

1616 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSIG1	AMFR	P26442	998
INSIG1	SCAP	Q12770	997
INSIG1	HMGCR	P04035	996
INSIG1	SREBF2	Q12772	952
INSIG1	PGRMC1	O00264	934
INSIG1	SREBF1	P36956	912
INSIG1	VCP	P55072	773
INSIG1	DHCR24	Q15392	770
INSIG1	HMGCS1	Q01581	762
INSIG1	IDI1	Q13907	739
INSIG1	RNF139	Q8WU17	733
INSIG1	CYP51A1	Q16850	718
INSIG1	HSD17B7	P56937	712
INSIG1	MLXIPL	Q9NP71	710
INSIG1	INS	P01308	702

IntAct

26 interactions, top by confidence:

A	B	Type	Score
INSIG1	AQP6	psi-mi:“MI:0915”(physical association)	0.560
INSIG1	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
CDH13	INSIG1	psi-mi:“MI:0914”(association)	0.530
HMGCR	INSIG1	psi-mi:“MI:0914”(association)	0.500
HMGCR	INSIG1	psi-mi:“MI:0915”(physical association)	0.500
INSIG1	AMFR	psi-mi:“MI:0915”(physical association)	0.500
INSIG1	SEC27	psi-mi:“MI:0407”(direct interaction)	0.440
	INSIG1	psi-mi:“MI:0407”(direct interaction)	0.440
INSIG1	SCAP	psi-mi:“MI:0915”(physical association)	0.400
INSIG1	CYP2C2	psi-mi:“MI:0915”(physical association)	0.400
CYP2C1	INSIG1	psi-mi:“MI:0915”(physical association)	0.400
CYP2C2	INSIG1	psi-mi:“MI:0915”(physical association)	0.400
COP1	INSIG1	psi-mi:“MI:0915”(physical association)	0.400
INSIG1	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
INSIG1	HTR2B	psi-mi:“MI:0915”(physical association)	0.370
INSIG1	ERLIN2	psi-mi:“MI:0914”(association)	0.350
INSIG1	MAP1A	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
INSIG1	TMEM237	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (176): INSIG1 (Affinity Capture-Western), INSIG1 (Synthetic Growth Defect), INSIG1 (Affinity Capture-Western), INSIG1 (Affinity Capture-MS), INSIG1 (Affinity Capture-Western), RNF145 (Affinity Capture-Western), SCAP (Affinity Capture-Western), SREBF2 (Affinity Capture-Western), AMFR (Affinity Capture-Western), INSIG1 (Affinity Capture-Western), SCAP (Affinity Capture-Western), INSIG1 (Affinity Capture-Western), INSIG1 (Two-hybrid), INSIG1 (Two-hybrid), INSIG1 (Two-hybrid)

ESM2 similar proteins: A0A087WTH1, A0A125YWU9, A0PK84, A6PVL3, C9JQL5, F1QHM7, F1QX91, O15503, O41933, O70418, O88728, P0DI73, P13164, P26376, Q01628, Q01629, Q08755, Q0II74, Q21642, Q32L65, Q3UNB8, Q3YBM2, Q5FVR1, Q5FWL7, Q5I0I2, Q5R8D6, Q5RF75, Q5Y5T3, Q6DHI1, Q76IC6, Q7M734, Q7TQJ1, Q8BGI3, Q8CES1, Q8CFA6, Q8IYP9, Q8N6L7, Q8WVZ1, Q91WU6, Q921C1

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

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RNF139	“down-regulates quantity”	INSIG1	ubiquitination
PRKAA1	“up-regulates quantity by stabilization”	INSIG1	phosphorylation
AMFR	“down-regulates quantity by destabilization”	INSIG1	ubiquitination
INSIG1	“down-regulates activity”	SCAP	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1703527	GRCh37/hg19 7q36.2-36.3(chr7:154831466-156356088)	Pathogenic

SpliceAI

1013 predictions. Top by Δscore:

Variant	Effect	Δscore
7:155298694:GCTG:G	donor_gain	1.0000
7:155298698:G:GG	donor_gain	1.0000
7:155298699:T:A	donor_loss	1.0000
7:155308237:ATAG:A	acceptor_gain	1.0000
7:155297956:CCAGG:C	donor_loss	0.9900
7:155297957:CAG:C	donor_loss	0.9900
7:155297958:AGGT:A	donor_loss	0.9900
7:155297959:GGTA:G	donor_loss	0.9900
7:155297960:G:T	donor_loss	0.9900
7:155297961:T:A	donor_loss	0.9900
7:155298634:G:GT	donor_gain	0.9900
7:155301565:GCT:G	acceptor_gain	0.9900
7:155301686:GTGCT:G	donor_gain	0.9900
7:155301715:TCCA:T	donor_gain	0.9900
7:155302418:G:GG	donor_gain	0.9900
7:155308237:ATAGG:A	acceptor_gain	0.9900
7:155308238:T:G	acceptor_gain	0.9900
7:155308239:AG:A	acceptor_gain	0.9900
7:155308240:GG:G	acceptor_gain	0.9900
7:155308240:GGGT:G	acceptor_gain	0.9900
7:155298693:AGCTG:A	donor_gain	0.9800
7:155298694:GCTGG:G	donor_gain	0.9800
7:155298695:CTG:C	donor_gain	0.9800
7:155298696:TG:T	donor_gain	0.9800
7:155298697:GG:G	donor_gain	0.9800
7:155301736:A:AG	donor_gain	0.9800
7:155308235:A:AG	acceptor_gain	0.9800
7:155308236:C:G	acceptor_gain	0.9800
7:155308239:A:AG	acceptor_gain	0.9800
7:155308240:G:GG	acceptor_gain	0.9800

AlphaMissense

1794 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:155298667:T:A	W128R	1.000
7:155298667:T:C	W128R	1.000
7:155298686:G:A	G134E	1.000
7:155301574:G:C	G141R	1.000
7:155301634:T:A	W161R	1.000
7:155301634:T:C	W161R	1.000
7:155301636:G:C	W161C	1.000
7:155301636:G:T	W161C	1.000
7:155301652:T:C	C167R	1.000
7:155301659:C:A	A169E	1.000
7:155301664:T:C	F171L	1.000
7:155301666:T:A	F171L	1.000
7:155301666:T:G	F171L	1.000
7:155301670:G:C	G173R	1.000
7:155301671:G:A	G173D	1.000
7:155301678:C:A	N175K	1.000
7:155301678:C:G	N175K	1.000
7:155302312:T:C	L200P	1.000
7:155302314:T:A	W201R	1.000
7:155302314:T:C	W201R	1.000
7:155302323:T:C	F204L	1.000
7:155302325:T:A	F204L	1.000
7:155302325:T:G	F204L	1.000
7:155302327:A:T	D205V	1.000
7:155302353:G:A	G214R	1.000
7:155302353:G:C	G214R	1.000
7:155302781:T:A	W247R	1.000
7:155302781:T:C	W247R	1.000
7:155302821:G:A	G260E	1.000
7:155298568:G:A	G95R	0.999

dbSNP variants (sampled 300 via entrez): RS1000353028 (7:155299280 A>G), RS1000957797 (7:155305604 G>A), RS1001354055 (7:155306932 G>A), RS1001400348 (7:155310274 G>A), RS1001631094 (7:155298722 G>A), RS1001994374 (7:155300576 C>G), RS1002119965 (7:155306234 A>G), RS1002430649 (7:155296606 TGACTGCGATGATCTAC>T), RS1002513589 (7:155296228 G>A), RS1002668013 (7:155296339 T>C), RS1003430776 (7:155308555 G>A,T), RS1003511684 (7:155307308 T>C), RS1003622390 (7:155303646 A>G), RS1003676870 (7:155301966 T>C), RS1003781359 (7:155297399 G>A,C)

Disease associations

OMIM: gene MIM:602055 | disease phenotypes: MIM:142945

GenCC curated gene-disease

Mondo (1): holoprosencephaly 3 (MONDO:0007733)

Orphanet (1): Holoprosencephaly (Orphanet:2162)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001549_4	Formal thought disorder in schizophrenia	7.000000e-06
GCST002397_2	Bladder cancer (smoking interaction)	2.000000e-06
GCST004524_3	Energy expenditure (24h)	3.000000e-06
GCST006479_37	Diverticular disease	4.000000e-06
GCST007680_4	Triiodothyronine levels and thyroxine levels	1.000000e-06
GCST008367_7	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	3.000000e-06
GCST008369_3	Plasma anti-thyroglobulin levels	9.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004805	formal thought disorder
EFO:0009959	diverticular disease
EFO:0008392	triiodothyronine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564181	Holoprosencephaly 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739841 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	6
Valproic Acid	affects expression, decreases expression, decreases methylation	6
Cyclosporine	increases expression, affects cotreatment, affects expression, decreases expression	6
bisphenol A	decreases methylation, increases expression, affects expression	5
fatostatin	increases reaction, increases response to substance, decreases expression	4
perfluorooctane sulfonic acid	decreases expression	3
Cisplatin	affects reaction, decreases expression, affects cotreatment, increases expression	3
Ethinyl Estradiol	increases expression, affects expression	3
Tetrachlorodibenzodioxin	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Cadmium Chloride	increases expression	3
cobaltous chloride	affects cotreatment, increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
tebuconazole	affects cotreatment, increases expression	2
Zoledronic Acid	increases expression	2
Copper	decreases expression, increases expression, affects binding	2
Estradiol	affects expression, increases expression	2
Hydrogen Peroxide	decreases expression, affects cotreatment, increases expression	2
Isoflavones	affects expression, increases expression	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance	2
Nickel	decreases expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Silicon Dioxide	increases expression	2
Tretinoin	increases expression, affects cotreatment, decreases expression	2
Tunicamycin	decreases expression	2
Thapsigargin	decreases expression, increases expression	2
Genistein	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance, increases expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4726294	Binding	Binding affinity to FLAG/myc-tagged Insig1 transfected in HEK293 cell membrane co-transfected with Flag-tagged human HMGCR-dCat-Eluc membrane domain (1 to 499 residues) at 20 uM preincubated for 30 mins followed by irradiation with UV light	Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7PB	SRD-14/pInsig-1	Transformed cell line	Female
CVCL_B7PE	SRD-15/pInsig-1	Transformed cell line	Female

Clinical trials (associated diseases)

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