NFE2L2 (Q16236) variants and mutations
NFE2L2 (also known as Q16236) is a human protein-coding gene encoding a nuclear factor erythroid 2-related factor 2 protein. It activates antioxidant, detoxification, and metabolic genes when released from KEAP1-mediated degradation. Somatic activating variants can lock cancer cells into a persistent stress-resistant state and promote therapy resistance. This analysis covers 1,568 NFE2L2 variants and mutations. Of these, 48% have computational variant effect predictions. Disease context includes immunodeficiency, developmental delay, and hypohomocysteinemia, hepatocellular carcinoma, and squamous cell lung carcinoma. Example NFE2L2 variants include M1?, M2I, and M2L.
Variant analysis overview
- Gene: NFE2L2
- Protein: Q16236
- UniProt accession: Q16236
- Organism: Homo sapiens
- Variants analyzed: 1568
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,304 unspecified-consequence records; 16 frameshift variants; 3 stop lost; 7 in-frame deletions; 123 synonymous variants; 109 missense variants; 1 in-frame insertions; 4 substitution
- Prediction scores: 759 variants have prediction scores (48% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: immunodeficiency, developmental delay, and hypohomocysteinemia, hepatocellular carcinoma, squamous cell lung carcinoma, Friedreich ataxia, head and neck squamous cell carcinoma, urinary bladder cancer, Abnormality of the skeletal system, lung carcinoma, esophageal squamous cell carcinoma, endometrial cancer, esophageal cancer, lymphoid neoplasm.
Protein structure and variant hotspots
- Protein features: 1 domains; 10 post-translational modification sites.
- Structural context: 133 variants have structural context.
- PTM context: 31 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable NFE2L2 variants
Examples include M1?, M2I, M2L, D3A, D3H, D3N, D3V, L4F. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- M2I (p.Met2Ile), TOPMed rs1690868904, REVEL 0.15, CADD 22.80
- M2L (p.Met2Leu), Ensembl rs2105503090, REVEL 0.19, CADD 22.80
- D3A (p.Asp3Ala), Ensembl rs2105503073
- D3H (p.Asp3His), TOPMed rs1690868838, Uncertain significance
- D3N (p.Asp3Asn), rs1690868838, ClinGen CA349389858, ClinVar RCV001961536, TOPMed rs1690868838, REVEL 0.10, CADD 23.90, Uncertain significance, not provided
- D3V (p.Asp3Val), Ensembl rs2105503073
- L4F (p.Leu4Phe), rs1308981355, ClinGen CA349389815, ClinVar RCV001895379, TOPMed rs1308981355, REVEL 0.06, CADD 23.00, Uncertain significance, not provided
- L4V (p.Leu4Val), TOPMed rs1391889890, REVEL 0.04, CADD 16.70, Likely benign
- E5D (p.Glu5Asp), Ensembl rs2105503053, REVEL 0.05, CADD 23.00
- E5V (p.Glu5Val), Ensembl rs754133211, REVEL 0.07, CADD 24.90
- L6M (p.Leu6Met), ExAC rs762231388, gnomAD rs762231388, REVEL 0.14, CADD 23.20
- P7L (p.Pro7Leu), gnomAD rs1423095854, REVEL 0.18, CADD 24.20
- P7S (p.Pro7Ser), TOPMed rs1182238326, gnomAD rs1182238326, REVEL 0.11, CADD 25.40
- P8S (p.Pro8Ser), gnomAD rs1202052968, REVEL 0.08, CADD 19.30
- P9A (p.Pro9Ala), gnomAD rs1281092624, REVEL 0.06, CADD 20.20
- P9S (p.Pro9Ser), gnomAD rs1281092624, REVEL 0.06, CADD 20.50
- P9T (p.Pro9Thr), gnomAD rs1281092624, REVEL 0.04, CADD 20.00
- L11F (p.Leu11Phe), gnomAD rs1690867684, REVEL 0.10, CADD 23.20
- L11P (p.Leu11Pro), TOPMed rs1690867613, REVEL 0.09, CADD 22.00
- P12L (p.Pro12Leu), ExAC rs771830842, TOPMed rs771830842, gnomAD rs771830842, REVEL 0.04, CADD 20.10
- P12Q (p.Pro12Gln), ExAC rs771830842, TOPMed rs771830842, gnomAD rs771830842, REVEL 0.07, CADD 18.60
- P12R (p.Pro12Arg), NCI-TCGA TCGA novel, REVEL 0.07, CADD 19.40, Variant assessed as somatic; moderate impact.
- Q14* (p.Gln14Ter), Ensembl rs1690867234, CADD 37.00
- Q14H (p.Gln14His), rs2105502961, ClinGen CA349389730, ClinVar RCV002047881, Ensembl rs2105502961, REVEL 0.09, CADD 24.40, Likely benign, not provided
- Q14R (p.Gln14Arg), 1000Genomes rs548183899, TOPMed rs548183899, gnomAD rs548183899, REVEL 0.07, CADD 28.50, Uncertain significance, not provided
- Q15* (p.Gln15Ter), gnomAD rs1417123664, CADD 55.00
- D16E (p.Asp16Glu), Ensembl rs2105459778
- D16G (p.Asp16Gly), Ensembl rs2105459784
- D16H (p.Asp16His), Ensembl rs1574260501
- D16N (p.Asp16Asn), Ensembl rs1574260501
- D16V (p.Asp16Val), Ensembl rs2105459784
- D16Y (p.Asp16Tyr), Ensembl rs1574260501
- M17I (p.Met17Ile), gnomAD rs1689665360
- M17K (p.Met17Lys), Ensembl rs2105459767
- M17L (p.Met17Leu), Ensembl rs2105459771
- M17T (p.Met17Thr), Ensembl rs2105459767
- M17V (p.Met17Val), Ensembl rs2105459771
- D18E (p.Asp18Glu), Ensembl rs2105459729, REVEL 0.12, CADD 21.50
- D18H (p.Asp18His), Ensembl rs2105459742
- D18N (p.Asp18Asn), Ensembl rs2105459742
- D18Y (p.Asp18Tyr), Ensembl rs2105459742
- L19* (p.Leu19Ter), Ensembl rs2105459723
- L19F (p.Leu19Phe), NCI-TCGA TCGA novel, gnomAD rs1689665249, REVEL 0.32, CADD 24.90, Variant assessed as somatic; moderate impact.
- L19S (p.Leu19Ser), Ensembl rs2105459723
- I20F (p.Ile20Phe), Ensembl rs2105459715
- I20M (p.Ile20Met), ExAC rs759238012, gnomAD rs759238012
- I20N (p.Ile20Asn), ExAC rs767333507, TOPMed rs767333507, gnomAD rs767333507
- I20S (p.Ile20Ser), ExAC rs767333507, TOPMed rs767333507, gnomAD rs767333507
- I20T (p.Ile20Thr), ExAC rs767333507, TOPMed rs767333507, gnomAD rs767333507, NCI-TCGA TCGA novel, REVEL 0.74, CADD 27.70, Variant assessed as somatic; high impact.
- I20V (p.Ile20Val), Ensembl rs2105459715
- D21E (p.Asp21Glu), Ensembl rs2105459683, REVEL 0.33, CADD 23.40
- D21G (p.Asp21Gly), Ensembl rs2105459692
- D21V (p.Asp21Val), Ensembl rs2105459692
- D21Y (p.Asp21Tyr), Ensembl rs866208249
- I22K (p.Ile22Lys), cosmic curated COSV67961, Ensembl rs2105459673
- I22L (p.Ile22Leu), gnomAD rs1231966037
- I22M (p.Ile22Met), Ensembl rs2105459666
- I22V (p.Ile22Val), gnomAD rs1231966037, Uncertain significance, not provided
- L23F (p.Leu23Phe), Ensembl rs2105459661, REVEL 0.54, CADD 26.50
- L23H (p.Leu23His), Ensembl rs2105459655
- L23P (p.Leu23Pro), Ensembl rs2105459655
- L23V (p.Leu23Val), cosmic curated COSV67962, Ensembl rs2105459661
- W24* (p.Trp24Ter), Ensembl rs2105459624, CADD 36.00
- W24C (p.Trp24Cys), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Ensembl rs2105459624, Likely oncogenic, Neoplasm
- W24G (p.Trp24Gly), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67963, Variant assessed as somatic; moderate impact.
- W24L (p.Trp24Leu), cosmic curated COSV10892, Ensembl rs1574260456
- W24R (p.Trp24Arg), rs1328994103, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, AlphaMissense 1.00, MetaLR 0.24, Uncertain significance, not provided
- W24S (p.Trp24Ser), cosmic curated COSV67961, Ensembl rs1574260456
- R25K (p.Arg25Lys), Ensembl rs1558981030, REVEL 0.14, CADD 19.80
- R25M (p.Arg25Met), Ensembl rs1558981030
- R25S (p.Arg25Ser), ExAC rs773805109, TOPMed rs773805109, gnomAD rs773805109, REVEL 0.32, CADD 24.10, Likely benign, not provided
- R25T (p.Arg25Thr), Ensembl rs1558981030
- Q26* (p.Gln26Ter), Ensembl rs2105459596
- Q26E (p.Gln26Glu), cosmic curated COSV67960, Ensembl rs2105459596
- Q26H (p.Gln26His), cosmic curated COSV67960, Ensembl rs2105459578
- Q26K (p.Gln26Lys), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Ensembl rs2105459596, Variant assessed as somatic; moderate impact.
- Q26L (p.Gln26Leu), NCI-TCGA Cosmic COSV1012, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Variant assessed as somatic; moderate impact.
- Q26P (p.Gln26Pro), NCI-TCGA Cosmic COSV1012, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Variant assessed as somatic; moderate impact.
- Q26R (p.Gln26Arg), NCI-TCGA Cosmic COSV1012, cosmic curated COSV10122, NCI-TCGA Cosmic COSV6796, Variant assessed as somatic; moderate impact.
- D27E (p.Asp27Glu), gnomAD rs1258630482, Likely benign
- D27H (p.Asp27His), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Variant assessed as somatic; moderate impact.
- D27N (p.Asp27Asn), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67962, Variant assessed as somatic; moderate impact.
- D27V (p.Asp27Val), cosmic curated COSV10972, Ensembl rs2105459568
- D27Y (p.Asp27Tyr), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Variant assessed as somatic; moderate impact.
- I28K (p.Ile28Lys), Ensembl rs2105459538
- I28L (p.Ile28Leu), gnomAD rs1441199966, REVEL 0.27, CADD 24.90
- I28M (p.Ile28Met), Ensembl rs2105459527
- I28T (p.Ile28Thr), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Ensembl rs2105459538, Uncertain significance, not provided
- I28V (p.Ile28Val), gnomAD rs1441199966, REVEL 0.10, CADD 21.10
- D29A (p.Asp29Ala), cosmic curated COSV67961, Ensembl rs1057519921
- D29E (p.Asp29Glu), Ensembl rs2105459500
- D29G (p.Asp29Gly), rs1057519921, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, AlphaMissense 0.95, MetaLR 0.24, Likely pathogenic
- D29H (p.Asp29His), rs1057519920, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, AlphaMissense 0.91, MetaLR 0.26, Likely pathogenic
- D29N (p.Asp29Asn), rs1057519920, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, AlphaMissense 0.91, MetaLR 0.26, Likely pathogenic
- D29V (p.Asp29Val), cosmic curated COSV67960, Ensembl rs1057519921
- D29Y (p.Asp29Tyr), rs1057519920, NCI-TCGA Cosmic COSV6796, AlphaMissense 0.91, MetaLR 0.26, Likely pathogenic
- L30F (p.Leu30Phe), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, TOPMed rs1689663660, Uncertain significance
- L30H (p.Leu30His), NCI-TCGA Cosmic COSV1012, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Likely pathogenic
- L30I (p.Leu30Ile), TOPMed rs1689663660, REVEL 0.32, CADD 26.50, Uncertain significance
- L30P (p.Leu30Pro), rs2105459482, ClinGen CA349381840, NCI-TCGA Cosmic COSV1012, cosmic curated COSV10122, AlphaMissense 0.93, MetaLR 0.28, Conflicting interpretations, not provided; Immunodeficiency, developmental delay, and hypohomocysteinemia
- L30R (p.Leu30Arg), NCI-TCGA Cosmic COSV1012, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Likely oncogenic, Neoplasm
- L30V (p.Leu30Val), rs1689663660, ClinGen CA349381845, ClinVar RCV001772816, TOPMed rs1689663660, REVEL 0.33, CADD 25.80, Uncertain significance, not provided
- G31R (p.Gly31Arg), rs1553488015, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, AlphaMissense 0.96, MetaLR 0.30, Pathogenic/Likely pathogenic, Immunodeficiency, developmental delay, and hypohomocysteinemia; Colorectal cance
- G31* (p.Gly31Ter), Ensembl rs1553488015, Pathogenic, in IMDDHH
- G31A (p.Gly31Ala), NCI-TCGA Cosmic COSV6795, cosmic curated COSV67959, NCI-TCGA Cosmic COSV6796, Variant assessed as somatic; moderate impact., in IMDDHH
- G31E (p.Gly31Glu), NCI-TCGA Cosmic COSV6795, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Variant assessed as somatic; moderate impact., in IMDDHH
- G31V (p.Gly31Val), NCI-TCGA Cosmic COSV6795, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Variant assessed as somatic; moderate impact., in IMDDHH
- G31G (p.Gly31Gly), gnomAD 2-177227942-A-G, CADD 1.80
- G31D (p.Gly31Asp), gnomAD 2-177227943-C-T, CADD 0.22
- G31S (p.Gly31Ser), gnomAD 2-177227944-C-T, CADD 0.61
- G31C (p.Gly31Cys), gnomAD 2-177227944-C-A, CADD 0.46
- V32E (p.Val32Glu), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Ensembl rs2105459426, Variant assessed as somatic; moderate impact.
- V32G (p.Val32Gly), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Ensembl rs2105459426, Variant assessed as somatic; moderate impact.
- V32I (p.Val32Ile), Ensembl rs2105459436, Uncertain significance, not provided
- V32L (p.Val32Leu), Ensembl rs2105459436
- S33R (p.Ser33Arg), Ensembl rs2105459403
- R34* (p.Arg34Ter), rs748696421, ClinGen CA349381737, cosmic curated COSV67960, ClinVar RCV003040632, CADD 1.82, Likely benign
- R34G (p.Arg34Gly), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, ExAC rs748696421, CADD 2.24, Likely oncogenic, Neoplasm
- R34L (p.Arg34Leu), cosmic curated COSV67961, Ensembl rs2105459389
- R34P (p.Arg34Pro), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Variant assessed as somatic; moderate impact.
- R34Q (p.Arg34Gln), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Uncertain significance, not provided
- R34R (p.Arg34Arg), gnomAD 2-177227948-T-C, CADD 1.36
- E35D (p.Glu35Asp), Ensembl rs2105459368, NCI-TCGA Cosmic COSV6796, cosmic curated COSV67961, Variant assessed as somatic; moderate impact.
- E35K (p.Glu35Lys), cosmic curated COSV10606, ExAC rs773182418, gnomAD rs773182418, REVEL 0.35, CADD 26.40
- E35* (p.Glu35Ter), cosmic curated COSV10750, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- E35Q (p.Glu35Gln), ExAC rs773182418, gnomAD rs773182418
- V36A (p.Val36Ala), Ensembl rs2105459354
- V36E (p.Val36Glu), Ensembl rs2105459354
- V36G (p.Val36Gly), Ensembl rs2105459354
- V36I (p.Val36Ile), gnomAD rs1256010315, REVEL 0.20, CADD 23.70
- V36L (p.Val36Leu), gnomAD rs1256010315
- V44del (p.Val44del), gnomAD 2-177227917-ATAC-, CADD 0.85
- V36V (p.Val36Val), rs994416264, gnomAD 2-177227918-T-G, CADD 2.82
- V36M (p.Val36Met), rs1238136386, gnomAD 2-177227923-C-T, CADD 0.27
- F37I (p.Phe37Ile), Ensembl rs2105459344
- F37L (p.Phe37Leu), Ensembl rs2105459336, CADD 0.61
- F37S (p.Phe37Ser), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67962, Variant assessed as somatic; moderate impact.
- F37Y (p.Phe37Tyr), Ensembl rs2105459339
- F37F (p.Phe37Phe), rs1173760516, gnomAD 2-177227939-G-A, CADD 0.50
- D38A (p.Asp38Ala), Ensembl rs2105459314
- D38H (p.Asp38His), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, Ensembl rs2105459323, Variant assessed as somatic; moderate impact.
- D38G (p.Asp38Gly), Ensembl rs2105459314
- D38N (p.Asp38Asn), Ensembl rs2105459323
- D38V (p.Asp38Val), NCI-TCGA TCGA novel, Ensembl rs2105459314, Variant assessed as somatic; moderate impact.
- D38Y (p.Asp38Tyr), Ensembl rs2105459323
- F39C (p.Phe39Cys), TOPMed rs1689663068
- F39I (p.Phe39Ile), Ensembl rs2105459306, REVEL 0.09, CADD 22.20
- F39S (p.Phe39Ser), cosmic curated COSV10122, TOPMed rs1689663068
- F39Y (p.Phe39Tyr), TOPMed rs1689663068
- S40C (p.Ser40Cys), Ensembl rs2105459290
- S40G (p.Ser40Gly), Ensembl rs2105459290
- S40I (p.Ser40Ile), Ensembl rs1689662982, REVEL 0.14, CADD 22.60
- S40N (p.Ser40Asn), cosmic curated COSV67962, Ensembl rs1689662982
- S40T (p.Ser40Thr), Ensembl rs1689662982
- Q41* (p.Gln41Ter), Ensembl rs2105459276
- Q41E (p.Gln41Glu), Ensembl rs2105459276
- Q41H (p.Gln41His), Ensembl rs2105459262
- Q41L (p.Gln41Leu), Ensembl rs2105459268, Uncertain significance, not provided
- Q41R (p.Gln41Arg), Ensembl rs2105459268
- Q41Q (p.Gln41Gln), gnomAD 2-177227945-C-T, CADD 1.46
- Q41P (p.Gln41Pro), gnomAD 2-177227946-T-G, CADD 0.91
- R42* (p.Arg42Ter), ExAC rs769685782, TOPMed rs769685782, gnomAD rs769685782, CADD 37.00
- R42G (p.Arg42Gly), ExAC rs769685782, TOPMed rs769685782, gnomAD rs769685782, CADD 3.10, Conflicting interpretations, not specified; not provided
- R42L (p.Arg42Leu), TOPMed rs1168551006, gnomAD rs1168551006
- R42P (p.Arg42Pro), TOPMed rs1168551006, gnomAD rs1168551006
- R42Q (p.Arg42Gln), cosmic curated COSV67961, TOPMed rs1168551006, gnomAD rs1168551006, REVEL 0.26, CADD 27.20, Uncertain significance, not provided
- R42R (p.Arg42Arg), gnomAD 2-177227924-C-T, CADD 1.43
- R42M (p.Arg42Met), gnomAD 2-177227925-C-A, CADD 1.09
- R42K (p.Arg42Lys), rs1425696891, gnomAD 2-177227925-C-T, CADD 1.44
- R43G (p.Arg43Gly), NCI-TCGA Cosmic COSV6796, cosmic curated COSV67960, 1000Genomes rs182428269, ESP rs182428269, Uncertain significance
- R43L (p.Arg43Leu), 1000Genomes rs35248500, ESP rs35248500, ExAC rs35248500, TOPMed rs35248500, REVEL 0.06, CADD 22.10, Benign
- R43P (p.Arg43Pro), 1000Genomes rs35248500, ESP rs35248500, ExAC rs35248500, TOPMed rs35248500, Benign
- R43Q (p.Arg43Gln), rs35248500, ClinGen CA161113, cosmic curated COSV67961, ClinVar RCV000121650, REVEL 0.06, CADD 14.80, Benign, not provided
- R43W (p.Arg43Trp), rs182428269, ClinGen CA161105, cosmic curated COSV10611, ClinVar RCV000121648, REVEL 0.12, CADD 25.00, Benign, not provided
- K44I (p.Lys44Ile), rs1255895060, ClinGen CA349381452, ClinVar RCV002303720, TOPMed rs1255895060, REVEL 0.41, CADD 27.30, Uncertain significance, not provided
- K44N (p.Lys44Asn), ExAC rs754673527, TOPMed rs754673527, gnomAD rs754673527
- E45D (p.Glu45Asp), gnomAD rs1237911287
- E45S (p.Glu45Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- E45V (p.Glu45Val), Ensembl rs2105459203
Public NFE2L2 analysis runs
- NFE2L2 analysis run — NFE2L2 (1,568 variants) — completed 2026-08-18