INSR

Chr 19ARAD

insulin receptor

Also known as: CD220, HHF5

NCBI Gene: 3643 ENSG00000171105 UniProt: P06213 OMIM: 147670

This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.454 OMIM phenotypes

Clinical Summary— INSR

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Gene-Disease Validity (ClinGen)

Donohue syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

76 unique Pathogenic / Likely Pathogenic· 341 VUS of 826 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — INSR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.45LOEUF

pLI 0.000

Z-score 5.19

OE 0.31 (0.22–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.83Z-score

OE missense 0.62 (0.58–0.67)

510 obs / 818.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.31 (0.22–0.45)

0≤0.351.4

Missense OE?0.62 (0.58–0.67)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 21 / 66.8Missense obs/exp: 510 / 818.5Syn Z: -0.85

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveINSR-related acanthosis nigricans and insulin resistance syndromeDNAD

definitiveINSR-related leprechaunismLOFAR

This gene — mechanism propensity

0.74top 25%

GOF

0.82top 10%

LOF

0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF1 literature citation · 42% of P/LP variants are LoF · LOEUF 0.45

GOFprediction above median

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

DNStudies with kinase-deficient insulin receptors transfected into cultured cells show that such receptors function as dominant-negative mutations and suppress the function of endogenous insulin receptors (review by Kahn and Goldstein, 1989).1

LOFSevere insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

826 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic29

VUS341

Likely Benign170

Benign150

Conflicting62

Pathogenic

Likely Pathogenic

341

VUS

170

Likely Benign

150

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	23	2	0	47
Likely Pathogenic	10	19	0	0	29
VUS	4	237	85	15	341
Likely Benign	0	12	56	102	170
Benign	0	3	134	13	150
Conflicting	—				62
Total	36	294	277	130	799

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap INSR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →