IRS2 (Insulin receptor substrate 2) variants and mutations
IRS2 (also known as Insulin receptor substrate 2) is a human protein-coding gene encoding an insulin receptor substrate 2 protein. It relays insulin and growth-factor signals in liver, pancreatic beta cells, brain, and other tissues, supporting metabolic control and cell survival. Altered signaling can contribute to insulin resistance and diabetes, but strong monogenic human disease associations are limited. This analysis covers 3,604 IRS2 variants and mutations. Of these, 73% have computational variant effect predictions. Disease context includes neurodegenerative disease, type 2 diabetes mellitus, and prostate carcinoma. Example IRS2 variants include S3G, S3N, and P4L.
Variant analysis overview
- Gene: IRS2
- Protein: Insulin receptor substrate 2
- UniProt accession: Q9Y4H2
- Organism: Homo sapiens
- Variants analyzed: 3604
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 3,284 unspecified-consequence records; 1 stop lost; 2 splice-region variants; 139 missense variants; 149 synonymous variants; 6 stop-gained variants; 13 frameshift variants; 7 in-frame deletions; 2 in-frame insertions; 1 substitution
- Prediction scores: 2,622 variants have prediction scores (73% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: neurodegenerative disease, type 2 diabetes mellitus, prostate carcinoma, cancer, lysosomal storage disease, diabetic retinopathy, diabetes mellitus, Abnormality of the skeletal system, diabetic eye disease, Parkinson disease, Limb pain, coronary atherosclerosis.
Protein structure and variant hotspots
- Protein features: 2 domains; 43 post-translational modification sites.
- Structural context: 457 variants have structural context.
- PTM context: 128 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable IRS2 variants
Examples include S3G, S3N, P4L, P4Q, P4S, P5R, R6L, R6P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- S3G (p.Ser3Gly), Ensembl rs2138940051, REVEL 0.09, CADD 20.10
- S3N (p.Ser3Asn), Ensembl rs2138940046, REVEL 0.11, CADD 22.50
- P4L (p.Pro4Leu), TOPMed rs1255092832, gnomAD rs1255092832, REVEL 0.10, CADD 22.60
- P4Q (p.Pro4Gln), TOPMed rs1255092832, gnomAD rs1255092832, REVEL 0.09, CADD 23.50
- P4S (p.Pro4Ser), Ensembl rs2138940037, REVEL 0.04, CADD 21.90
- P5R (p.Pro5Arg), TOPMed rs1437882425
- R6L (p.Arg6Leu), Ensembl rs1877914276, REVEL 0.02, CADD 4.07
- R6P (p.Arg6Pro), Ensembl rs1877914276
- R6Q (p.Arg6Gln), Ensembl rs1877914276, REVEL 0.03, CADD 6.58
- H7N (p.His7Asn), gnomAD rs1277967516, REVEL 0.08, CADD 6.74
- H7P (p.His7Pro), rs1877914130, ClinGen CA388663979, ClinVar RCV004078535, Ensembl rs1877914130, AlphaMissense 0.08, MetaLR 0.05, Uncertain significance, not specified
- H7Q (p.His7Gln), 1000Genomes rs1210016272, gnomAD rs1210016272, REVEL 0.05, CADD 2.83
- H7R (p.His7Arg), Ensembl rs1877914130, REVEL 0.03, AlphaMissense 0.08, Uncertain significance
- H7Y (p.His7Tyr), gnomAD rs1277967516, REVEL 0.07, CADD 9.33
- G8E (p.Gly8Glu), rs2138939986, ClinGen CA388663972, ClinVar RCV004092533, Ensembl rs2138939986, REVEL 0.02, CADD 15.80, Uncertain significance, not specified
- G8R (p.Gly8Arg), TOPMed rs1348529090, gnomAD rs1348529090, REVEL 0.03, CADD 18.70
- G8V (p.Gly8Val), Ensembl rs2138939986, REVEL 0.04, CADD 15.40, Uncertain significance
- G8W (p.Gly8Trp), TOPMed rs1348529090, gnomAD rs1348529090, REVEL 0.10, CADD 21.00
- P9S (p.Pro9Ser), TOPMed rs1409660082, REVEL 0.02, CADD 3.38
- P10L (p.Pro10Leu), TOPMed rs1472186130, gnomAD rs1472186130, REVEL 0.02, CADD 15.60
- G11R (p.Gly11Arg), Ensembl rs2138939958, REVEL 0.03, CADD 10.70
- G11V (p.Gly11Val), Ensembl rs2138939955, REVEL 0.01, CADD 7.07
- G11W (p.Gly11Trp), Ensembl rs2138939958, REVEL 0.08, CADD 17.30
- P12L (p.Pro12Leu), gnomAD rs1022312372, REVEL 0.11, CADD 5.62, Uncertain significance
- P12Q (p.Pro12Gln), gnomAD rs1022312372, REVEL 0.08, CADD 7.32, Uncertain significance
- P12R (p.Pro12Arg), rs1022312372, ClinGen CA388663947, ClinVar RCV004090941, gnomAD rs1022312372, REVEL 0.06, CADD 7.26, Uncertain significance, not specified
- A13V (p.Ala13Val), Ensembl rs2138939915, REVEL 0.06, CADD 13.00
- S14G (p.Ser14Gly), Ensembl rs1877913046, REVEL 0.03, CADD 5.41
- S14I (p.Ser14Ile), TOPMed rs1309855258, gnomAD rs1309855258, REVEL 0.02, CADD 6.84
- S14N (p.Ser14Asn), TOPMed rs1309855258, gnomAD rs1309855258, REVEL 0.04, CADD 3.01
- S14R (p.Ser14Arg), Ensembl rs1877912890, REVEL 0.04, CADD 6.67
- G15A (p.Gly15Ala), TOPMed rs895227588, gnomAD rs895227588, REVEL 0.06, CADD 19.10
- G15E (p.Gly15Glu), TOPMed rs895227588, gnomAD rs895227588, REVEL 0.03, CADD 20.30
- G15R (p.Gly15Arg), gnomAD rs1279752588, REVEL 0.06, CADD 20.10
- D16A (p.Asp16Ala), Ensembl rs2138939885
- D16E (p.Asp16Glu), ExAC rs749425733, gnomAD rs749425733, REVEL 0.08, CADD 13.20
- D16G (p.Asp16Gly), Ensembl rs2138939885, REVEL 0.06, CADD 17.30
- D16Y (p.Asp16Tyr), Ensembl rs2138939892, REVEL 0.08, CADD 21.70
- G17R (p.Gly17Arg), TOPMed rs1476561196, gnomAD rs1476561196, REVEL 0.10, CADD 23.50
- G17S (p.Gly17Ser), TOPMed rs1476561196, gnomAD rs1476561196, REVEL 0.07, CADD 17.50
- P18S (p.Pro18Ser), TOPMed rs1877912292, REVEL 0.07, CADD 14.10
- N19S (p.Asn19Ser), Ensembl rs2138939859, REVEL 0.07, CADD 11.50
- N19T (p.Asn19Thr), Ensembl rs2138939859
- L20F (p.Leu20Phe), TOPMed rs1435824732, gnomAD rs1435824732, REVEL 0.10, CADD 16.70
- L20H (p.Leu20His), Ensembl rs2138939853, REVEL 0.09, CADD 17.20
- N21I (p.Asn21Ile), Ensembl rs2138939842, REVEL 0.09, CADD 14.70
- N21K (p.Asn21Lys), Ensembl rs2138939839, REVEL 0.03, CADD 13.80
- N21S (p.Asn21Ser), Ensembl rs2138939842, REVEL 0.08, CADD 7.71
- N22H (p.Asn22His), gnomAD rs1361411930, REVEL 0.04, CADD 17.30
- N22I (p.Asn22Ile), gnomAD rs1157639287, REVEL 0.07, CADD 22.80
- N22S (p.Asn22Ser), NCI-TCGA Cosmic COSV1010, REVEL 0.06, CADD 16.40, Variant assessed as somatic; moderate impact.
- N23H (p.Asn23His), Ensembl rs2138939813
- N23I (p.Asn23Ile), Ensembl rs2138939809
- N24S (p.Asn24Ser), gnomAD rs1877911894, REVEL 0.07, CADD 15.60
- N25D (p.Asn25Asp), NCI-TCGA TCGA novel, REVEL 0.02, CADD 15.90, Variant assessed as somatic; moderate impact.
- N26S (p.Asn26Ser), Ensembl rs1877911747, REVEL 0.05, CADD 18.10
- N27H (p.Asn27His), Ensembl rs2138939791, REVEL 0.05, CADD 15.10
- N27S (p.Asn27Ser), Ensembl rs1877911659, REVEL 0.05, CADD 15.00
- N28H (p.Asn28His), ExAC rs769951329, TOPMed rs769951329, gnomAD rs769951329, REVEL 0.07, CADD 15.70
- N28I (p.Asn28Ile), Ensembl rs2138939762
- H29Y (p.His29Tyr), TOPMed rs1037219199, gnomAD rs1037219199, REVEL 0.03, CADD 16.40
- S30G (p.Ser30Gly), ExAC rs748054510, TOPMed rs748054510, gnomAD rs748054510, REVEL 0.02, CADD 14.20
- S30R (p.Ser30Arg), TOPMed rs1486272348, gnomAD rs1486272348, REVEL 0.01, CADD 19.50
- V31A (p.Val31Ala), Ensembl rs2138939721
- V31E (p.Val31Glu), Ensembl rs2138939721
- V31G (p.Val31Gly), Ensembl rs2138939721
- V31M (p.Val31Met), gnomAD rs1474364815, REVEL 0.48, CADD 24.90
- R32C (p.Arg32Cys), Ensembl rs2138939715, REVEL 0.36, CADD 25.10
- R32H (p.Arg32His), Ensembl rs2138939710, REVEL 0.29, CADD 24.30
- K33E (p.Lys33Glu), Ensembl rs2138939708, REVEL 0.42, CADD 23.70
- K33M (p.Lys33Met), TOPMed rs1048711377, REVEL 0.58, CADD 27.90
- K33R (p.Lys33Arg), TOPMed rs1048711377, REVEL 0.34, CADD 24.40
- C34G (p.Cys34Gly), Ensembl rs2138939696
- C34R (p.Cys34Arg), Ensembl rs2138939696
- C34S (p.Cys34Ser), Ensembl rs2138939696
- C34W (p.Cys34Trp), Ensembl rs2138939684, REVEL 0.56, CADD 26.70
- C34Y (p.Cys34Tyr), Ensembl rs2138939691
- G35A (p.Gly35Ala), Ensembl rs866827171
- G35C (p.Gly35Cys), rs2501619444, ClinGen CA388663787, ClinVar RCV003911468, REVEL 0.95, CADD 27.40, Uncertain significance, IRS2-related disorder
- G35D (p.Gly35Asp), Ensembl rs866827171, REVEL 0.91, CADD 25.00
- R38C (p.Arg38Cys), TOPMed rs1213621000, gnomAD rs1213621000, REVEL 0.40, CADD 25.30
- R38H (p.Arg38His), Ensembl rs2138939667, REVEL 0.31, CADD 23.30
- R38S (p.Arg38Ser), TOPMed rs1213621000, gnomAD rs1213621000, REVEL 0.33, CADD 22.80
- K39* (p.Lys39Ter), Ensembl rs2138939660, CADD 36.00
- Q40* (p.Gln40Ter), Ensembl rs2138939651, CADD 36.00
- Q40E (p.Gln40Glu), Ensembl rs2138939651
- Q40R (p.Gln40Arg), Ensembl rs2138939648, REVEL 0.36, CADD 25.20
- K41Q (p.Lys41Gln), TOPMed rs1327405067, gnomAD rs1327405067, REVEL 0.40, CADD 26.10
- K41R (p.Lys41Arg), 1000Genomes rs2138939637, REVEL 0.21, CADD 23.50
- H42L (p.His42Leu), TOPMed rs1877909378
- H42N (p.His42Asn), TOPMed rs1877909468, gnomAD rs1877909468
- H42Y (p.His42Tyr), TOPMed rs1877909468, gnomAD rs1877909468, REVEL 0.26, CADD 23.30
- G43D (p.Gly43Asp), rs1284382975, TOPMed rs1284382975, gnomAD rs1284382975, REVEL 0.50, CADD 23.80, Variant assessed as somatic; moderate impact.
- G43V (p.Gly43Val), TOPMed rs1284382975, gnomAD rs1284382975, REVEL 0.37, CADD 22.40
- H44P (p.His44Pro), Ensembl rs2138939617
- H44R (p.His44Arg), Ensembl rs2138939617
- H44Y (p.His44Tyr), ExAC rs751359671, gnomAD rs751359671, REVEL 0.67, CADD 26.00
- K45* (p.Lys45Ter), NCI-TCGA TCGA novel, gnomAD rs1292992712, Variant assessed as somatic; high impact.
- K45E (p.Lys45Glu), gnomAD rs1292992712
- K45M (p.Lys45Met), TOPMed rs921690150, gnomAD rs921690150
- K45N (p.Lys45Asn), TOPMed rs1381868281, gnomAD rs1381868281, REVEL 0.42, CADD 23.50
- K45Q (p.Lys45Gln), gnomAD rs1292992712, REVEL 0.43, CADD 24.80
- K45R (p.Lys45Arg), TOPMed rs921690150, gnomAD rs921690150, REVEL 0.07, CADD 22.50
- R46C (p.Arg46Cys), gnomAD rs1287607728, REVEL 0.90, CADD 32.00
- R46H (p.Arg46His), Ensembl rs2138939601, REVEL 0.87, CADD 27.60
- R46S (p.Arg46Ser), gnomAD rs1287607728, REVEL 0.90, CADD 28.20
- F47I (p.Phe47Ile), Ensembl rs2138939593
- F47L (p.Phe47Leu), Ensembl rs2138939593, REVEL 0.50, CADD 18.50
- F47S (p.Phe47Ser), Ensembl rs2138939586, REVEL 0.62, CADD 26.10
- F47V (p.Phe47Val), Ensembl rs2138939593, REVEL 0.63, CADD 24.50
- F48L (p.Phe48Leu), Ensembl rs2138939578, REVEL 0.75, CADD 23.50
- F48S (p.Phe48Ser), Ensembl rs2138939581, REVEL 0.76, CADD 26.80
- V49G (p.Val49Gly), Ensembl rs2138939574
- V49L (p.Val49Leu), Ensembl rs2138939577, REVEL 0.80, CADD 23.90
- L50P (p.Leu50Pro), Ensembl rs2138939565, REVEL 0.79, CADD 23.80
- R51C (p.Arg51Cys), gnomAD rs1345817777, REVEL 0.53, CADD 24.60
- R51H (p.Arg51His), TOPMed rs1877908226, REVEL 0.52, CADD 24.30
- G52* (p.Gly52Ter), TOPMed rs1222652819, CADD 36.00
- G52A (p.Gly52Ala), TOPMed rs1594393161, gnomAD rs1594393161, REVEL 0.14, CADD 18.10
- G52R (p.Gly52Arg), TOPMed rs1222652819, REVEL 0.39, CADD 24.20
- P53L (p.Pro53Leu), Ensembl rs2138939539, REVEL 0.13, CADD 23.80
- P53T (p.Pro53Thr), TOPMed rs1460016841, gnomAD rs1460016841, REVEL 0.07, CADD 20.80
- G54C (p.Gly54Cys), gnomAD rs1166002006, REVEL 0.47, CADD 23.30
- G54D (p.Gly54Asp), TOPMed rs1424157764, gnomAD rs1424157764, REVEL 0.39, CADD 23.10
- G54R (p.Gly54Arg), gnomAD rs1166002006, REVEL 0.40, CADD 23.20
- G54S (p.Gly54Ser), gnomAD rs1166002006, REVEL 0.23, CADD 21.00
- G54V (p.Gly54Val), TOPMed rs1424157764, gnomAD rs1424157764, REVEL 0.41, CADD 23.00
- A55E (p.Ala55Glu), ExAC rs758017473, TOPMed rs758017473, gnomAD rs758017473, REVEL 0.08, CADD 15.40
- A55G (p.Ala55Gly), ExAC rs758017473, TOPMed rs758017473, gnomAD rs758017473, REVEL 0.04, CADD 15.80
- A55T (p.Ala55Thr), gnomAD rs1877907525, REVEL 0.02, CADD 13.40
- A55V (p.Ala55Val), ExAC rs758017473, TOPMed rs758017473, gnomAD rs758017473, REVEL 0.03, CADD 17.00
- G56D (p.Gly56Asp), gnomAD rs1485515924, REVEL 0.12, CADD 14.50
- G56V (p.Gly56Val), gnomAD rs1485515924, REVEL 0.11, CADD 14.20
- G57A (p.Gly57Ala), TOPMed rs1248043947, gnomAD rs1248043947, REVEL 0.06, CADD 14.40
- G57D (p.Gly57Asp), TOPMed rs1248043947, gnomAD rs1248043947, REVEL 0.15, CADD 15.00
- D58A (p.Asp58Ala), Ensembl rs2138939503
- D58E (p.Asp58Glu), Ensembl rs2138939498, REVEL 0.04, CADD 15.30
- D58G (p.Asp58Gly), Ensembl rs2138939503
- D58N (p.Asp58Asn), NCI-TCGA TCGA novel, REVEL 0.03, CADD 17.50, Variant assessed as somatic; moderate impact.
- E59G (p.Glu59Gly), Ensembl rs2138939487, REVEL 0.03, CADD 20.80
- E59K (p.Glu59Lys), NCI-TCGA TCGA novel, gnomAD rs1877906847, REVEL 0.06, CADD 18.70, Variant assessed as somatic; moderate impact.
- E59Q (p.Glu59Gln), gnomAD rs1877906847, REVEL 0.05, CADD 16.90
- A60S (p.Ala60Ser), Ensembl rs2138939484, REVEL 0.01, CADD 15.20
- A60V (p.Ala60Val), Ensembl rs1594393125, REVEL 0.06, CADD 17.90
- T61A (p.Thr61Ala), Ensembl rs2138939468
- T61M (p.Thr61Met), ExAC rs750038928, TOPMed rs750038928, gnomAD rs750038928, REVEL 0.07, CADD 21.90
- T61P (p.Thr61Pro), NCI-TCGA TCGA novel, Ensembl rs2138939468, Variant assessed as somatic; moderate impact.
- T61R (p.Thr61Arg), ExAC rs750038928, TOPMed rs750038928, gnomAD rs750038928, REVEL 0.02, CADD 17.10
- T61S (p.Thr61Ser), Ensembl rs2138939468
- A62G (p.Ala62Gly), TOPMed rs1273204122, gnomAD rs1273204122
- A62V (p.Ala62Val), TOPMed rs1273204122, gnomAD rs1273204122, REVEL 0.03, CADD 18.70
- G63C (p.Gly63Cys), Ensembl rs2138939446
- G63V (p.Gly63Val), Ensembl rs2138939441
- G64R (p.Gly64Arg), ExAC rs756734259, TOPMed rs756734259, gnomAD rs756734259, REVEL 0.16, CADD 25.30
- G64W (p.Gly64Trp), NCI-TCGA Cosmic COSV1010, ExAC rs756734259, TOPMed rs756734259, gnomAD rs756734259, REVEL 0.19, CADD 26.40, Variant assessed as somatic; moderate impact.
- G65E (p.Gly65Glu), TOPMed rs1293916243, gnomAD rs1293916243, REVEL 0.12, CADD 23.80
- G65V (p.Gly65Val), TOPMed rs1293916243, gnomAD rs1293916243, REVEL 0.03, CADD 22.10
- S66A (p.Ser66Ala), ExAC rs372367471, gnomAD rs372367471, REVEL 0.01, CADD 17.10
- S66L (p.Ser66Leu), Ensembl rs2138939417, REVEL 0.06, CADD 18.60
- S66W (p.Ser66Trp), Ensembl rs2138939417, REVEL 0.04, CADD 23.70
- A67G (p.Ala67Gly), TOPMed rs1877905950
- A67V (p.Ala67Val), TOPMed rs1877905950, REVEL 0.05, CADD 20.70
- P68A (p.Pro68Ala), Ensembl rs1877905789
- P68L (p.Pro68Leu), 1000Genomes rs2138939394, REVEL 0.07, CADD 22.60
- P68Q (p.Pro68Gln), 1000Genomes rs2138939394, REVEL 0.11, CADD 23.80
- P68R (p.Pro68Arg), 1000Genomes rs2138939394
- P68S (p.Pro68Ser), Ensembl rs1877905789, REVEL 0.03, CADD 19.10
- Q69H (p.Gln69His), gnomAD rs1393901694
- Q69K (p.Gln69Lys), gnomAD rs1438789170, REVEL 0.04, CADD 20.20
- Q69P (p.Gln69Pro), Ensembl rs2138939371
- P70L (p.Pro70Leu), TOPMed rs1165891062, gnomAD rs1165891062, REVEL 0.52, CADD 23.60
- P70Q (p.Pro70Gln), NCI-TCGA TCGA novel, TOPMed rs1165891062, gnomAD rs1165891062, REVEL 0.43, CADD 23.30, Variant assessed as somatic; moderate impact.
- P70R (p.Pro70Arg), TOPMed rs1165891062, gnomAD rs1165891062
- P70S (p.Pro70Ser), gnomAD rs1415372702, REVEL 0.39, CADD 23.10
- P70T (p.Pro70Thr), gnomAD rs1415372702, REVEL 0.50, CADD 23.10
- P71L (p.Pro71Leu), Ensembl rs2138939358
- R72W (p.Arg72Trp), TOPMed rs1877905253, REVEL 0.74, CADD 29.00
- L73H (p.Leu73His), Ensembl rs2138939329
- L73P (p.Leu73Pro), Ensembl rs2138939329
- L73V (p.Leu73Val), Ensembl rs2138939335, REVEL 0.61, CADD 24.40
Public IRS2 analysis runs
- IRS2 analysis run — IRS2 (3,604 variants) — completed 2026-08-20