IRS1
Chr 2ADinsulin receptor substrate 1
Also known as: HIRS-1
The insulin receptor substrate 1 protein serves as a signaling adapter that is phosphorylated by insulin and insulin-like growth factor I receptors, functioning as a scaffold to propagate downstream signaling pathways critical for glucose homeostasis, lipid metabolism, growth, and development. Mutations cause autosomal dominant susceptibility to type 2 diabetes mellitus and insulin resistance. This gene is not highly constrained against loss-of-function variants, consistent with its role in disease susceptibility rather than severe developmental disorders.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
232 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 1 | 23 | 0 | 24 |
Likely Pathogenic | 0 | 0 | 2 | 0 | 2 |
VUS | 0 | 164 | 4 | 0 | 168 |
Likely Benign | 0 | 7 | 2 | 9 | 18 |
Benign | 0 | 4 | 1 | 8 | 13 |
Conflicting | — | 1 | |||
| Total | 0 | 176 | 32 | 17 | 226 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
IRS1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools