INSIG1

Chr 7

insulin induced gene 1

Also known as: CL6

NCBI Gene: 3638ENSG00000186480UniProt: O15503

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. [provided by RefSeq, Oct 2016]

33
ClinVar variants
33
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— INSIG1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic of 33 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.12LOEUF
pLI 0.001
Z-score 1.31
OE 0.57 (0.31–1.12)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.90Z-score
OE missense 0.57 (0.48–0.68)
91 obs / 158.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.31–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.48–0.68)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.77
0≤1.21.6
LoF obs/exp: 6 / 10.6Missense obs/exp: 91 / 158.3Syn Z: 1.45

ClinVar Variant Classifications

33 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic1
32
Pathogenic
1
Likely Pathogenic

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————32
Likely Pathogenic
————1
VUS
————0
Likely Benign
————0
Benign
————0
Total—33

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

INSIG1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway.
Zheng ZG et al.·Autophagy
2021
A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer.
Xiong L et al.·Mol Cancer
2023
Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression.
Fu Y et al.·J Clin Invest
2025
Targeting piRNA-137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma.
Zhan Y et al.·Adv Sci (Weinh)
2025
Tubular insulin-induced gene 1 deficiency promotes NAD(+) consumption and exacerbates kidney fibrosis.
Li S et al.·EMBO Mol Med
2024
Saikosaponin D attenuates metabolic associated fatty liver disease by coordinately tuning PPARα and INSIG/SREBP1c pathway.
Gu Y et al.·Phytomedicine
2022
Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression.
Azzu V et al.·Mol Metab
2021Functional
Identification of hub biomarkers in liver post-metabolic and bariatric surgery using comprehensive machine learning (experimental studies).
Li Z et al.·Int J Surg
2025
Exploring the potential association and experimental validation of disrupted circadian rhythms with polycystic ovary syndrome via meta-analysis and bioinformatics: a possible pathogenic mechanism.
Li W et al.·Front Endocrinol (Lausanne)
2025Meta-analysis
Progesterone Receptor Membrane Component 1 and its Accomplice: Emerging Therapeutic Targets in Lung Cancer.
Solairaja S et al.·Endocr Metab Immune Disord Drug Targets
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools