TCF7L2 (Transcription factor 7-like 2) variants and mutations
TCF7L2 (also known as Transcription factor 7-like 2) is a human protein-coding gene encoding a transcription factor 7-like 2 protein. It mediates Wnt-dependent transcription and also influences pancreatic, hepatic, and intestinal programs involved in glucose metabolism. Common intronic variants at this locus are among the strongest and most reproducible genetic risk factors for type 2 diabetes. This analysis covers 2,522 TCF7L2 variants and mutations. Of these, 26% have computational variant effect predictions. Disease context includes type 2 diabetes mellitus, colorectal adenocarcinoma, and prostate carcinoma. Example TCF7L2 variants include M1?, P2A, and P2L.
Variant analysis overview
- Gene: TCF7L2
- Protein: Transcription factor 7-like 2
- UniProt accession: Q9NQB0
- Organism: Homo sapiens
- Variants analyzed: 2522
- Variant scope: all variants
- Completed: 2026-08-19
Variant and mutation evidence
- Variant composition: 2,352 unspecified-consequence records; 88 missense variants; 62 synonymous variants; 5 stop-gained variants; 3 in-frame deletions; 4 splice-region variants; 7 frameshift variants; 1 substitution
- Prediction scores: 656 variants have prediction scores (26% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: type 2 diabetes mellitus, colorectal adenocarcinoma, prostate carcinoma, diabetes mellitus, breast carcinoma, myopia, type 1 diabetes mellitus, colon adenocarcinoma, coronary artery disorder, gestational diabetes, diabetic retinopathy, colorectal cancer.
Protein structure and variant hotspots
- Protein features: 2 post-translational modification sites.
- PTM context: 9 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.
Notable TCF7L2 variants
Examples include M1?, P2A, P2L, P2R, P2S, P2T, P2Q, P2P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV10740, cosmic curated COSV10967, cosmic curated COSV60510, cosmic curated COSV10590
- P2A (p.Pro2Ala), Ensembl rs2134175969
- P2L (p.Pro2Leu), cosmic curated COSV10466, Ensembl rs2134175991, CADD 25.90, PolyPhen-2 0.89
- P2R (p.Pro2Arg), Ensembl rs2134175991
- P2S (p.Pro2Ser), Ensembl rs2134175969, CADD 25.70, PolyPhen-2 0.99
- P2T (p.Pro2Thr), Ensembl rs2134175969
- P2Q (p.Pro2Gln), gnomAD 10-112950761-C-A, CADD 25.50, PolyPhen-2 0.99
- P2P (p.Pro2Pro), rs2134176006, gnomAD 10-112950762-G-A, CADD 20.10
- Q3* (p.Gln3Ter), cosmic curated COSV10466, Ensembl rs2134176022
- Q3E (p.Gln3Glu), Ensembl rs2134176022
- Q3H (p.Gln3His), gnomAD rs1420003331
- Q3K (p.Gln3Lys), Ensembl rs2134176022, CADD 25.40, PolyPhen-2 0.99
- Q3L (p.Gln3Leu), Ensembl rs2134176047
- L4P (p.Leu4Pro), Ensembl rs2134176129, CADD 29.00, PolyPhen-2 1.00
- L4Q (p.Leu4Gln), Ensembl rs2134176129
- L4V (p.Leu4Val), 1000Genomes rs182211983, ESP rs182211983, ExAC rs182211983, TOPMed rs182211983
- L4L (p.Leu4Leu), rs182211983, gnomAD 10-112950766-C-T, CADD 18.30
- N5D (p.Asn5Asp), Ensembl rs2134176158
- N5I (p.Asn5Ile), Ensembl rs2134176174
- N5K (p.Asn5Lys), ESP rs369343242, ExAC rs369343242, TOPMed rs369343242, gnomAD rs369343242
- N5S (p.Asn5Ser), Ensembl rs2134176174
- N5N (p.Asn5Asn), rs369343242, gnomAD 10-112950771-C-T, CADD 19.10
- G6A (p.Gly6Ala), Ensembl rs2134176246
- G6C (p.Gly6Cys), gnomAD rs1437908566, CADD 28.00, PolyPhen-2 1.00
- G6R (p.Gly6Arg), gnomAD rs1437908566
- G6S (p.Gly6Ser), gnomAD rs1437908566, CADD 23.30, PolyPhen-2 0.81
- G6V (p.Gly6Val), gnomAD 10-112950773-G-T, CADD 27.30, PolyPhen-2 0.99
- G6G (p.Gly6Gly), rs1589556610, gnomAD 10-112950774-C-G, CADD 19.90
- G7D (p.Gly7Asp), Ensembl rs2134176299, CADD 24.60, PolyPhen-2 1.00
- G7R (p.Gly7Arg), gnomAD rs1294078020
- G7S (p.Gly7Ser), cosmic curated COSV10887, gnomAD rs1294078020, CADD 28.10, PolyPhen-2 1.00
- G7C (p.Gly7Cys), gnomAD 10-112950775-G-T, CADD 29.70, PolyPhen-2 1.00
- G7G (p.Gly7Gly), rs770908287, gnomAD 10-112950777-T-G, CADD 19.90
- G8* (p.Gly8Ter), cosmic curated COSV60509, Ensembl rs2134176336
- G8A (p.Gly8Ala), Ensembl rs2134176364
- G8M (p.Gly8Met), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G8R (p.Gly8Arg), Ensembl rs2134176336
- G8V (p.Gly8Val), gnomAD 10-112950779-G-T, CADD 28.00, PolyPhen-2 1.00
- G8G (p.Gly8Gly), rs113219338, gnomAD 10-112950780-A-G, CADD 19.30
- G9E (p.Gly9Glu), cosmic curated COSV60508, gnomAD rs1429045243, CADD 27.30, PolyPhen-2 1.00
- G9R (p.Gly9Arg), Ensembl rs2134176396, Uncertain significance, not provided
- G9W (p.Gly9Trp), gnomAD 10-112950781-G-T, CADD 29.90, PolyPhen-2 1.00
- G9A (p.Gly9Ala), gnomAD 10-112950782-G-C, CADD 26.50, PolyPhen-2 1.00
- G9V (p.Gly9Val), gnomAD 10-112950782-G-T, CADD 27.10, PolyPhen-2 1.00
- G9G (p.Gly9Gly), gnomAD 10-112950783-G-A, CADD 18.10
- D10A (p.Asp10Ala), Ensembl rs188153157
- D10E (p.Asp10Glu), Ensembl rs2134176478, CADD 23.60, PolyPhen-2 1.00
- D10G (p.Asp10Gly), Ensembl rs188153157
- D10H (p.Asp10His), Ensembl rs2134176446
- D10N (p.Asp10Asn), Ensembl rs2134176446
- D10V (p.Asp10Val), Ensembl rs188153157
- D10D (p.Asp10Asp), gnomAD 10-112950786-T-C, CADD 20.00
- D11A (p.Asp11Ala), Ensembl rs2134176526
- D11E (p.Asp11Glu), ExAC rs759111159, gnomAD rs759111159
- D11G (p.Asp11Gly), Ensembl rs2134176526
- D11H (p.Asp11His), Ensembl rs2134176504
- D11N (p.Asp11Asn), Ensembl rs2134176504
- D11V (p.Asp11Val), Ensembl rs2134176526
- D11Y (p.Asp11Tyr), Ensembl rs2134176504, CADD 29.50, PolyPhen-2 0.99
- D11D (p.Asp11Asp), rs759111159, gnomAD 10-112950789-C-T, CADD 19.60
- L12I (p.Leu12Ile), Ensembl rs2030733334, CADD 24.80, PolyPhen-2 1.00
- L12L (p.Leu12Leu), rs2030733334, gnomAD 10-112950790-C-T, CADD 19.60
- G13A (p.Gly13Ala), Ensembl rs2134176629
- G13C (p.Gly13Cys), Ensembl rs2134176614
- G13D (p.Gly13Asp), Ensembl rs2134176629, CADD 27.90, PolyPhen-2 1.00
- G13V (p.Gly13Val), cosmic curated COSV60508, Ensembl rs2134176629
- G13G (p.Gly13Gly), rs1408409202, gnomAD 10-112950795-C-A, CADD 19.30
- A14G (p.Ala14Gly), Ensembl rs2134176676
- A14T (p.Ala14Thr), gnomAD 10-112950796-G-A, CADD 28.90, PolyPhen-2 1.00
- A14S (p.Ala14Ser), gnomAD 10-112950796-G-T, CADD 27.10, PolyPhen-2 1.00
- N15H (p.Asn15His), gnomAD rs1227970748, CADD 26.80, PolyPhen-2 1.00
- N15I (p.Asn15Ile), 1000Genomes rs1287908784, TOPMed rs1287908784, gnomAD rs1287908784
- N15K (p.Asn15Lys), 1000Genomes rs76088094, ESP rs76088094, ExAC rs76088094, TOPMed rs76088094, CADD 25.60, PolyPhen-2 1.00, Benign
- N15S (p.Asn15Ser), 1000Genomes rs1287908784, TOPMed rs1287908784, gnomAD rs1287908784, CADD 23.80, PolyPhen-2 0.99
- N15Y (p.Asn15Tyr), gnomAD rs1227970748
- N15N (p.Asn15Asn), rs76088094, gnomAD 10-112950801-C-T, CADD 20.60
- D16E (p.Asp16Glu), cosmic curated COSV10590, Ensembl rs2134176819
- D16G (p.Asp16Gly), Ensembl rs2134176803
- D16H (p.Asp16His), Ensembl rs2134176779
- D16N (p.Asp16Asn), Ensembl rs2134176779
- D16V (p.Asp16Val), Ensembl rs2134176803
- D16Y (p.Asp16Tyr), cosmic curated COSV60504
- E17* (p.Glu17Ter), cosmic curated COSV60503, CADD 38.00
- E17D (p.Glu17Asp), Ensembl rs2134176880
- E17G (p.Glu17Gly), Ensembl rs2134176868
- E17K (p.Glu17Lys), cosmic curated COSV60508, Ensembl rs2134176852, CADD 31.00, PolyPhen-2 1.00
- E17Q (p.Glu17Gln), Ensembl rs2134176852
- L18M (p.Leu18Met), ExAC rs762639760, gnomAD rs762639760, CADD 19.50, PolyPhen-2 0.11
- L18P (p.Leu18Pro), Ensembl rs2134176914
- L18Q (p.Leu18Gln), Ensembl rs2134176914
- L18V (p.Leu18Val), ExAC rs762639760, gnomAD rs762639760, CADD 24.30, PolyPhen-2 0.45
- I19F (p.Ile19Phe), Ensembl rs2134176958
- I19L (p.Ile19Leu), Ensembl rs2134176958
- I19M (p.Ile19Met), Ensembl rs2134177001
- I19N (p.Ile19Asn), Ensembl rs2134176978
- I19S (p.Ile19Ser), Ensembl rs2134176978
- S20C (p.Ser20Cys), gnomAD rs1456854681, CADD 26.60, PolyPhen-2 0.97
- S20F (p.Ser20Phe), gnomAD rs1456854681
- S20T (p.Ser20Thr), Ensembl rs2134177025
- S20Y (p.Ser20Tyr), gnomAD rs1456854681
- S20S (p.Ser20Ser), rs764425409, gnomAD 10-112950816-C-T, CADD 20.10
- F21I (p.Phe21Ile), Ensembl rs2134177098
- F21L (p.Phe21Leu), TOPMed rs1377100649, NCI-TCGA TCGA novel, CADD 27.70, PolyPhen-2 1.00, Variant assessed as somatic; moderate impact.
- F21S (p.Phe21Ser), Ensembl rs2134177119
- F21Y (p.Phe21Tyr), Ensembl rs2134177119
- K22* (p.Lys22Ter), cosmic curated COSV10466, Ensembl rs2134177158
- K22Q (p.Lys22Gln), gnomAD 10-112950820-A-C, CADD 23.20, PolyPhen-2 0.42
- K22K (p.Lys22Lys), rs369358979, gnomAD 10-112950822-A-G, CADD 21.40
- D23E (p.Asp23Glu), Ensembl rs2134177230, cosmic curated COSV60509, CADD 26.10, PolyPhen-2 1.00
- D23G (p.Asp23Gly), Ensembl rs2134177203
- D23H (p.Asp23His), Ensembl rs2134177180
- D23N (p.Asp23Asn), Ensembl rs2134177180
- D23V (p.Asp23Val), Ensembl rs2134177203
- E24* (p.Glu24Ter), NCI-TCGA Cosmic COSV6050, cosmic curated COSV60507, Ensembl rs2134177245, Variant assessed as somatic; high impact.
- E24D (p.Glu24Asp), Ensembl rs2134177271, CADD 23.80, PolyPhen-2 1.00
- E24G (p.Glu24Gly), Ensembl rs2134177268
- E24K (p.Glu24Lys), cosmic curated COSV60506, Ensembl rs2134177245
- E24Q (p.Glu24Gln), cosmic curated COSV10058, Ensembl rs2134177245
- G25A (p.Gly25Ala), gnomAD rs2030739506
- G25C (p.Gly25Cys), Ensembl rs2134177281
- G25D (p.Gly25Asp), gnomAD rs2030739506, CADD 28.40, PolyPhen-2 1.00
- G25R (p.Gly25Arg), Ensembl rs2134177281
- G25S (p.Gly25Ser), Ensembl rs2134177281
- G25V (p.Gly25Val), gnomAD rs2030739506
- G25G (p.Gly25Gly), rs757636212, gnomAD 10-112950831-C-T, CADD 20.30
- E26G (p.Glu26Gly), cosmic curated COSV60505, Ensembl rs2134177376
- E26K (p.Glu26Lys), Ensembl rs2134177358, CADD 29.90, PolyPhen-2 0.74
- E26Q (p.Glu26Gln), NCI-TCGA Cosmic COSV6050, cosmic curated COSV60503, Ensembl rs2134177358, Variant assessed as somatic; moderate impact.
- E26* (p.Glu26Ter), gnomAD 10-112950832-G-T, CADD 37.00
- E26E (p.Glu26Glu), rs768080592, gnomAD 10-112950834-A-G, CADD 19.20
- Q27E (p.Gln27Glu), Ensembl rs1564697131
- Q27H (p.Gln27His), gnomAD rs1411132876, CADD 22.50, PolyPhen-2 0.32
- Q27K (p.Gln27Lys), Ensembl rs1564697131, CADD 25.10, PolyPhen-2 0.56
- Q27L (p.Gln27Leu), Ensembl rs2030741586
- Q27P (p.Gln27Pro), gnomAD 10-112950836-A-C, CADD 27.20, PolyPhen-2 0.95
- Q27Q (p.Gln27Gln), gnomAD 10-112950837-G-A, CADD 19.90
- E28* (p.Glu28Ter), cosmic curated COSV60510
- E28D (p.Glu28Asp), rs373425129, 1000Genomes rs373425129, ESP rs373425129, ExAC rs373425129, CADD 22.60, PolyPhen-2 0.03, Likely benign, Inborn genetic diseases
- E28K (p.Glu28Lys), Ensembl rs2134177455
- E28Q (p.Glu28Gln), rs2134177455, ClinGen CA378531463, ClinVar RCV003422884, AlphaMissense 0.58, MetaLR 0.96, Uncertain significance, not provided
- E28G (p.Glu28Gly), gnomAD 10-112950839-A-G, CADD 32.00, PolyPhen-2 0.67
- E28E (p.Glu28Glu), rs373425129, gnomAD 10-112950840-G-A, CADD 20.40
- E29D (p.Glu29Asp), Ensembl rs2134177507, CADD 23.20, PolyPhen-2 0.52
- E29K (p.Glu29Lys), Ensembl rs2134177489
- E29Q (p.Glu29Gln), Ensembl rs2134177489, CADD 28.10, PolyPhen-2 0.98
- E29del (p.Glu29del), rs754968616, gnomAD 10-112950835-CAGG, CADD 21.80
- E29* (p.Glu29Ter), gnomAD 10-112950841-G-T, CADD 37.00
- E29V (p.Glu29Val), gnomAD 10-112950842-A-T, CADD 31.00, PolyPhen-2 0.99
- K30* (p.Lys30Ter), ExAC rs780321853, TOPMed rs780321853, gnomAD rs780321853
- K30E (p.Lys30Glu), ExAC rs780321853, TOPMed rs780321853, gnomAD rs780321853, CADD 24.60, PolyPhen-2 0.00
- K30M (p.Lys30Met), Ensembl rs936392357
- K30N (p.Lys30Asn), cosmic curated COSV60504, Ensembl rs192341583
- K30Q (p.Lys30Gln), ExAC rs780321853, TOPMed rs780321853, gnomAD rs780321853, CADD 24.40, PolyPhen-2 0.03
- K30R (p.Lys30Arg), Ensembl rs936392357
- K30K (p.Lys30Lys), rs192341583, gnomAD 10-112950846-G-A, CADD 20.50
- S31G (p.Ser31Gly), cosmic curated COSV10524, ExAC rs754099726, TOPMed rs754099726, gnomAD rs754099726, CADD 23.30, PolyPhen-2 0.03
- S31N (p.Ser31Asn), TOPMed rs2030745750, CADD 22.00, PolyPhen-2 0.00
- S31R (p.Ser31Arg), Ensembl rs2134177601, CADD 22.10, PolyPhen-2 0.07
- S31I (p.Ser31Ile), gnomAD 10-112950848-G-T, CADD 19.30, PolyPhen-2 0.00
- S32C (p.Ser32Cys), cosmic curated COSV10967
- S32F (p.Ser32Phe), cosmic curated COSV60503
- S32P (p.Ser32Pro), cosmic curated COSV60505, Ensembl rs2134177630
- S32T (p.Ser32Thr), Ensembl rs2134177630
- S32Y (p.Ser32Tyr), Ensembl rs2134177654
- S32S (p.Ser32Ser), rs755319058, gnomAD 10-112950852-C-T, CADD 16.50
- E33G (p.Glu33Gly), ESP rs148876270, ExAC rs148876270, TOPMed rs148876270, gnomAD rs148876270, CADD 23.70, PolyPhen-2 0.02, Likely benign, Inborn genetic diseases
- E33K (p.Glu33Lys), cosmic curated COSV10466, Ensembl rs2134177703
- E33Q (p.Glu33Gln), Ensembl rs2134177703, CADD 25.60, PolyPhen-2 0.88
- N34D (p.Asn34Asp), ExAC rs746837026, TOPMed rs746837026, gnomAD rs746837026, CADD 23.60, PolyPhen-2 0.20
- N34H (p.Asn34His), ExAC rs746837026, TOPMed rs746837026, gnomAD rs746837026, CADD 23.60
- N34I (p.Asn34Ile), Ensembl rs2134177760
- N34S (p.Asn34Ser), Ensembl rs2134177760
- N34T (p.Asn34Thr), Ensembl rs2134177760
- N34Y (p.Asn34Tyr), ExAC rs746837026, TOPMed rs746837026, gnomAD rs746837026
- S35C (p.Ser35Cys), ExAC rs776204265, TOPMed rs776204265, gnomAD rs776204265, CADD 24.40, PolyPhen-2 0.92
- S35F (p.Ser35Phe), ExAC rs776204265, TOPMed rs776204265, gnomAD rs776204265
- S35P (p.Ser35Pro), cosmic curated COSV60510, Ensembl rs2134177812
- S35T (p.Ser35Thr), Ensembl rs2134177812
- S35Y (p.Ser35Tyr), ExAC rs776204265, TOPMed rs776204265, gnomAD rs776204265
- S36* (p.Ser36Ter), cosmic curated COSV60503, gnomAD rs1282664682
Public TCF7L2 analysis runs
- TCF7L2 analysis run — TCF7L2 (2,522 variants) — completed 2026-08-19