IRS1

Chr 2AD

insulin receptor substrate 1

Also known as: HIRS-1

NCBI Gene: 3667 ENSG00000169047 UniProt: P35568 OMIM: 147545

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.501 OMIM phenotype

Clinical Summary— IRS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 167 VUS of 209 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — IRS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.50LOEUF

pLI 0.024

Z-score 3.69

OE 0.29 (0.17–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.94–1.05)

787 obs / 792.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.17–0.50)

0≤0.351.4

Missense OE?0.99 (0.94–1.05)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 9 / 31.3Missense obs/exp: 787 / 792.4Syn Z: 0.12

This gene — mechanism propensity

0.6260th %ile

GOF

0.4874th %ile

LOF

0.51top 25%

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.

DNprediction above median

GOF1 literature citation

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

GOFGenomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 28801450 ↗

ClinVar Variant Classifications

209 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS167

Likely Benign19

Benign12

Conflicting1

Pathogenic

167

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	2	0	4
Likely Pathogenic	0	0	0	0	0
VUS	0	166	1	0	167
Likely Benign	0	8	0	11	19
Benign	0	4	1	7	12
Conflicting	—				1
Total	0	180	4	18	203

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap IRS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →