FOXA2 (Hepatocyte nuclear factor 3-beta) variants and mutations
FOXA2 (also known as Hepatocyte nuclear factor 3-beta) is a human protein-coding gene encoding a hepatocyte nuclear factor 3-beta protein. It establishes and maintains transcriptional programs in endoderm-derived organs and the nervous system, including liver, pancreas, lung, and dopaminergic neurons. Heterozygous pathogenic variants can cause developmental disorders involving the pancreas, pituitary, and central nervous system. This analysis covers 868 FOXA2 variants and mutations. Of these, 70% have computational variant effect predictions. Disease context includes hypothyroidism, nodular goiter, and nontoxic goiter. Example FOXA2 variants include M1T, G3R, and G9E.
Variant analysis overview
- Gene: FOXA2
- Protein: Hepatocyte nuclear factor 3-beta
- UniProt accession: Q9Y261
- Organism: Homo sapiens
- Variants analyzed: 868
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 315 unspecified-consequence records; 1 stop lost; 7 in-frame deletions; 128 synonymous variants; 378 missense variants; 19 frameshift variants; 17 stop-gained variants; 2 in-frame insertions; 1 substitution
- Prediction scores: 604 variants have prediction scores (70% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hypothyroidism, nodular goiter, nontoxic goiter, endometrial cancer, type 2 diabetes mellitus, multinodular goiter, non-acquired combined pituitary hormone deficiency, toxic multinodular goitre, thyroid gland disorder, Combined pituitary hormone deficiencies, genetic forms, combined pituitary hormone deficiencies, genetic form, gestational diabetes.
Protein structure and variant hotspots
- Protein features: 10 post-translational modification sites.
- PTM context: 40 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 FOXA2 variants
Examples include M1T, G3R, G9E, G9R, E11*, S13T, D14N, S17R. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1T (p.Met1Thr), rs2514816036, ClinGen CA408503420, ClinVar RCV002665290, Uncertain significance, Inborn genetic diseases
- G3R (p.Gly3Arg), cosmic curated COSV10749
- G9E (p.Gly9Glu), cosmic curated COSV10971, NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G9R (p.Gly9Arg), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- E11* (p.Glu11Ter), rs368038185, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65795, ClinGen CA408503354, AlphaMissense 0.90, MetaLR 0.85, Uncertain significance
- S13T (p.Ser13Thr), cosmic curated COSV65795
- D14N (p.Asp14Asn), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- S17R (p.Ser17Arg), rs2514815977, ClinGen CA408503311, ClinVar RCV003068212, Likely benign, not provided
- Y18N (p.Tyr18Asn), cosmic curated COSV10971
- A20T (p.Ala20Thr), cosmic curated COSV65796
- Y25C (p.Tyr25Cys), rs2514814570, ClinGen CA408503242, ClinVar RCV003844099, Uncertain significance, not provided
- S29I (p.Ser29Ile), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65795, Variant assessed as somatic; moderate impact.
- N30K (p.Asn30Lys), cosmic curated COSV10531
- M31I (p.Met31Ile), cosmic curated COSV10891, Ensembl rs2122995764
- M31L (p.Met31Leu), cosmic curated COSV65795, gnomAD rs1984647807
- G34S (p.Gly34Ser), cosmic curated COSV10749
- L35V (p.Leu35Val), rs2514814471, ClinGen CA408503176, ClinVar RCV003406133, Uncertain significance, FOXA2-related disorder
- G36K (p.Gly36Lys), cosmic curated COSV10531
- M37I (p.Met37Ile), cosmic curated COSV65795, REVEL 0.80, CADD 26.30
- N38D (p.Asn38Asp), cosmic curated COSV65796
- N38H (p.Asn38His), rs1247284954, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, AlphaMissense 0.26, MetaLR 0.14, Variant assessed as somatic; moderate impact.
- G39D (p.Gly39Asp), cosmic curated COSV10971
- M44I (p.Met44Ile), cosmic curated COSV65795, TOPMed rs1984645400, gnomAD rs1984645400
- M44V (p.Met44Val), cosmic curated COSV10100, TOPMed rs1403066399, gnomAD rs1403066399
- S45R (p.Ser45Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- M46R (p.Met46Arg), cosmic curated COSV10971
- S47* (p.Ser47Ter), cosmic curated COSV65796
- A49D (p.Ala49Asp), cosmic curated COSV10891
- A50G (p.Ala50Gly), cosmic curated COSV65795, TOPMed rs1339440179, gnomAD rs1339440179
- G52S (p.Gly52Ser), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65795, Variant assessed as somatic; moderate impact.
- S53G (p.Ser53Gly), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- G54D (p.Gly54Asp), cosmic curated COSV65796, Conflicting interpretations, not provided; Inborn genetic diseases
- S59R (p.Ser59Arg), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, REVEL 0.05, CADD 22.10, Variant assessed as somatic; moderate impact.
- A60S (p.Ala60Ser), cosmic curated COSV65795
- A60T (p.Ala60Thr), rs769823311, NCI-TCGA Cosmic COSV6579, ExAC rs769823311, gnomAD rs769823311, AlphaMissense 0.07, MetaLR 0.56, Variant assessed as somatic; moderate impact.
- G61A (p.Gly61Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G61V (p.Gly61Val), rs868573695, []
- S62F (p.Ser62Phe), cosmic curated COSV65796
- S66* (p.Ser66Ter), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; high impact.
- M73I (p.Met73Ile), cosmic curated COSV65796
- S76F (p.Ser76Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L77M (p.Leu77Met), cosmic curated COSV65795
- A78S (p.Ala78Ser), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65797, Variant assessed as somatic; moderate impact.
- G79E (p.Gly79Glu), cosmic curated COSV10593, 1000Genomes rs2122994948
- M80I (p.Met80Ile), rs1338942089, ClinGen CA408502888, ClinVar RCV003827131, AlphaMissense 0.43, MetaLR 0.10, Uncertain significance, not provided
- S81F (p.Ser81Phe), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- G83R (p.Gly83Arg), cosmic curated COSV65796
- G85S (p.Gly85Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A86S (p.Ala86Ser), cosmic curated COSV10971
- M87I (p.Met87Ile), cosmic curated COSV65796
- A88E (p.Ala88Glu), rs755036513, ClinGen CA9787069, cosmic curated COSV10749, ClinVar RCV002698623, AlphaMissense 0.50, MetaLR 0.06, Conflicting interpretations, Inborn genetic diseases; not provided
- A88T (p.Ala88Thr), rs748287662, ClinGen CA9787071, cosmic curated COSV10971, ClinVar RCV003364315, AlphaMissense 0.09, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- G92S (p.Gly92Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S93A (p.Ser93Ala), rs2514813897, ClinGen CA408502818, ClinVar RCV002727984, Uncertain significance, Inborn genetic diseases
- S93L (p.Ser93Leu), rs200457711, ClinGen CA313137800, cosmic curated COSV10749, ClinVar RCV002626755, AlphaMissense 0.53, MetaLR 0.56, Uncertain significance, not provided; Inborn genetic diseases
- A96E (p.Ala96Glu), rs752266641, ClinGen CA9787062, cosmic curated COSV65795, ClinVar RCV002905225, AlphaMissense 0.41, MetaLR 0.03, Uncertain significance, Inborn genetic diseases
- G98R (p.Gly98Arg), cosmic curated COSV10971, REVEL 0.44, CADD 25.10
- G101D (p.Gly101Asp), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G101S (p.Gly101Ser), cosmic curated COSV10593
- L106F (p.Leu106Phe), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L106M (p.Leu106Met), cosmic curated COSV10749, TOPMed rs1328153871, gnomAD rs1328153871
- S107G (p.Ser107Gly), cosmic curated COSV10100
- S109N (p.Ser109Asn), rs200211848, ClinGen CA9787057, cosmic curated COSV65796, ClinVar RCV002129800, AlphaMissense 0.20, MetaLR 0.08, Benign, not provided
- P112L (p.Pro112Leu), rs1433544606, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65797, TOPMed rs1433544606, AlphaMissense 0.48, MetaLR 0.09, Variant assessed as somatic; moderate impact.
- G114V (p.Gly114Val), cosmic curated COSV10531, 1000Genomes rs372510372, ESP rs372510372, ExAC rs372510372, Likely benign
- G115R (p.Gly115Arg), cosmic curated COSV10749
- A117S (p.Ala117Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A117T (p.Ala117Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- A117V (p.Ala117Val), cosmic curated COSV65797, TOPMed rs1984629676, gnomAD rs1984629676
- G122S (p.Gly122Ser), cosmic curated COSV65796, ExAC rs765955954, gnomAD rs765955954
- G123C (p.Gly123Cys), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- A125V (p.Ala125Val), rs775592057, NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, 1000Genomes rs775592057, AlphaMissense 0.15, MetaLR 0.06, Uncertain significance
- P126L (p.Pro126Leu), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- Y127H (p.Tyr127His), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- M130I (p.Met130Ile), cosmic curated COSV65795
- M133I (p.Met133Ile), rs1000920736, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65797, TOPMed rs1000920736, AlphaMissense 0.35, MetaLR 0.07, Variant assessed as somatic; moderate impact.
- S134R (p.Ser134Arg), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- P135A (p.Pro135Ala), cosmic curated COSV99058
- M136H (p.Met136His), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- M136P (p.Met136Pro), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G138R (p.Gly138Arg), cosmic curated COSV10749, ExAC rs755715343, TOPMed rs755715343, gnomAD rs755715343
- A145S (p.Ala145Ser), cosmic curated COSV10100, gnomAD rs1420783959
- A145T (p.Ala145Thr), NCI-TCGA Cosmic COSV1010, Variant assessed as somatic; moderate impact.
- A145V (p.Ala145Val), cosmic curated COSV10749, TOPMed rs1322289080, gnomAD rs1322289080
- R146H (p.Arg146His), cosmic curated COSV10469
- D147E (p.Asp147Glu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D147Y (p.Asp147Tyr), rs2514813442, ClinGen CA408502497, ClinVar RCV003352256, Uncertain significance, Inborn genetic diseases
- P148S (p.Pro148Ser), rs771400505, ExAC rs771400505, gnomAD rs771400505, AlphaMissense 0.11, MetaLR 0.08, Variant assessed as somatic; moderate impact.
- R153C (p.Arg153Cys), cosmic curated COSV65796, TOPMed rs955822437, gnomAD rs955822437
- R153G (p.Arg153Gly), rs955822437, NCI-TCGA Cosmic COSV6579, TOPMed rs955822437, gnomAD rs955822437, AlphaMissense 0.99, MetaLR 0.61, Variant assessed as somatic; moderate impact.
- S154R (p.Ser154Arg), cosmic curated COSV65797
- Y155C (p.Tyr155Cys), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- H157A (p.His157Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- H157Q (p.His157Gln), rs144279222, NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, ESP rs144279222, AlphaMissense 1.00, MetaLR 0.53, Uncertain significance, Inborn genetic diseases
- A158S (p.Ala158Ser), rs745424789, NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, AlphaMissense 0.78, MetaLR 0.48, Uncertain significance, Inborn genetic diseases
- A158T (p.Ala158Thr), cosmic curated COSV65796
- P160L (p.Pro160Leu), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Uncertain significance, Combined pituitary hormone deficiencies, genetic form
- Y162C (p.Tyr162Cys), cosmic curated COSV65795
- S163L (p.Ser163Leu), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65797, Variant assessed as somatic; moderate impact.
- S163T (p.Ser163Thr), cosmic curated COSV10823
- S163W (p.Ser163Trp), rs2514813303, ClinGen CA408502392, ClinVar RCV003228600, Likely pathogenic, Congenital syndromic hypopituitarism
- I165V (p.Ile165Val), cosmic curated COSV65797
- S166L (p.Ser166Leu), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Ensembl rs2122993451, Variant assessed as somatic; moderate impact.
- L167R (p.Leu167Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- M170I (p.Met170Ile), cosmic curated COSV10971
- M170W (p.Met170Trp), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- A171T (p.Ala171Thr), cosmic curated COSV65796
- A171V (p.Ala171Val), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Ensembl rs2122993423, Variant assessed as somatic; moderate impact.
- Q173* (p.Gln173Ter), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; high impact.
- Q173H (p.Gln173His), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- Q174H (p.Gln174His), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65797, Variant assessed as somatic; moderate impact.
- N177D (p.Asn177Asp), cosmic curated COSV10823, TOPMed rs1416604142
- N177Q (p.Asn177Gln), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K178T (p.Lys178Thr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- M179I (p.Met179Ile), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- T181T (p.Thr181Thr), gnomAD 20-22582681-C-T, CADD 6.36
- L182Q (p.Leu182Gln), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- L182V (p.Leu182Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S183R (p.Ser183Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S183S (p.Ser183Ser), rs2122993293, gnomAD 20-22582675-G-A, CADD 12.50
- S183T (p.Ser183Thr), gnomAD 20-22582676-C-G, REVEL 0.63, CADD 23.50
- E184G (p.Glu184Gly), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- E184K (p.Glu184Lys), cosmic curated COSV10593
- E184E (p.Glu184Glu), rs759791855, gnomAD 20-22582672-C-T, CADD 12.30
- I185N (p.Ile185Asn), cosmic curated COSV10593
- W188* (p.Trp188Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- W188C (p.Trp188Cys), gnomAD 20-22582660-C-G, REVEL 0.92, CADD 31.00
- W188S (p.Trp188Ser), gnomAD 20-22582661-C-G, REVEL 0.88, CADD 31.00
- I189I (p.Ile189Ile), gnomAD 20-22582657-G-T, CADD 13.20
- I189F (p.Ile189Phe), rs1984619322, gnomAD 20-22582659-T-A, REVEL 0.96, CADD 30.00
- I189V (p.Ile189Val), gnomAD 20-22582671-T-C, REVEL 0.80, CADD 24.00
- I189L (p.Ile189Leu), gnomAD 20-22582671-T-G, REVEL 0.88, CADD 27.50
- M190V (p.Met190Val), cosmic curated COSV65796, ESP rs376209663, ExAC rs376209663, TOPMed rs376209663
- M190I (p.Met190Ile), rs200970860, gnomAD 20-22582654-C-A, REVEL 0.82, CADD 24.20
- M190T (p.Met190Thr), gnomAD 20-22582655-A-G, REVEL 0.90, CADD 24.50
- M190K (p.Met190Lys), gnomAD 20-22582655-A-T, REVEL 0.93, CADD 25.00
- D191D (p.Asp191Asp), rs1218985577, gnomAD 20-22582651-G-A, CADD 11.40
- L192I (p.Leu192Ile), cosmic curated COSV10823
- L192Q (p.Leu192Gln), gnomAD 20-22582677-TCA-T, CADD 33.00
- L192* (p.Leu192Ter), gnomAD 20-22582680-GC-G, CADD 18.00
- P194A (p.Pro194Ala), rs2514813129, ClinGen CA408502174, ClinVar RCV003073260, Uncertain significance, not provided
- P194L (p.Pro194Leu), NCI-TCGA Cosmic COSV6579, cosmic curated COSV65796, Variant assessed as somatic; moderate impact.
- P194P (p.Pro194Pro), rs1984618794, gnomAD 20-22582642-G-A, CADD 12.60
- F195L (p.Phe195Leu), cosmic curated COSV65796
- F195V (p.Phe195Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- F195F (p.Phe195Phe), rs1984618704, gnomAD 20-22582639-G-A, CADD 13.30
- Y196Y (p.Tyr196Tyr), gnomAD 20-22582636-G-A, CADD 9.59
- R197L (p.Arg197Leu), rs372773557, NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, ESP rs372773557, AlphaMissense 0.98, MetaLR 0.87, Uncertain significance
- R197Q (p.Arg197Gln), rs372773557, ClinGen CA9786990, NCI-TCGA Cosmic COSV1010, cosmic curated COSV65796, AlphaMissense 0.98, MetaLR 0.87, Uncertain significance, not provided
- Q198R (p.Gln198Arg), gnomAD 20-22582664-T-C, REVEL 0.81, CADD 27.60
- Q198* (p.Gln198Ter), gnomAD 20-22582665-G-A, CADD 40.00
- Q200* (p.Gln200Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q201P (p.Gln201Pro), rs2514813093, ClinGen CA408502122, ClinVar RCV003203191, Uncertain significance, Inborn genetic diseases
- R202C (p.Arg202Cys), cosmic curated COSV10606, Ensembl rs2122993141
- R202H (p.Arg202His), cosmic curated COSV10971, Ensembl rs2122993133
- R202R (p.Arg202Arg), rs1984618489, gnomAD 20-22582633-C-T, CADD 14.10
- R202L (p.Arg202Leu), rs372773557, gnomAD 20-22582634-C-A, REVEL 0.93, AlphaMissense 0.98
- R202G (p.Arg202Gly), gnomAD 20-22582635-G-C, REVEL 0.91, CADD 25.00
- W203* (p.Trp203Ter), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q204R (p.Gln204Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Q204Q (p.Gln204Gln), rs772638884, gnomAD 20-22582612-C-T, CADD 11.50
- Q204H (p.Gln204His), gnomAD 20-22582612-C-A, REVEL 0.91, CADD 24.90
- Q204K (p.Gln204Lys), gnomAD 20-22582623-G-T, REVEL 0.67, CADD 24.90
- N205K (p.Asn205Lys), gnomAD 20-22582627-G-T, REVEL 0.74, CADD 25.70
- N205N (p.Asn205Asn), rs773886523, gnomAD 20-22582627-G-A, CADD 11.20
- S206F (p.Ser206Phe), cosmic curated COSV65796
- I207L (p.Ile207Leu), cosmic curated COSV65795, ExAC rs769397287, gnomAD rs769397287
- I207M (p.Ile207Met), cosmic curated COSV65795
- I207T (p.Ile207Thr), cosmic curated COSV65795, ExAC rs745498650, gnomAD rs745498650
- R208C (p.Arg208Cys), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, REVEL 0.85, CADD 32.00, Variant assessed as somatic; moderate impact.
- R208H (p.Arg208His), cosmic curated COSV65796
- H209Y (p.His209Tyr), cosmic curated COSV65796
- S210W (p.Ser210Trp), cosmic curated COSV10593, NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L211F (p.Leu211Phe), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- S212F (p.Ser212Phe), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10100, Variant assessed as somatic; moderate impact.
- S212S (p.Ser212Ser), gnomAD 20-22582594-C-G, CADD 10.10
- S212C (p.Ser212Cys), gnomAD 20-22582607-G-C, REVEL 0.98, CADD 29.30
- S212P (p.Ser212Pro), rs774841083, gnomAD 20-22582608-A-G, REVEL 0.96, CADD 30.00
- S212T (p.Ser212Thr), gnomAD 20-22582608-A-T, REVEL 0.92, CADD 27.10
- N214K (p.Asn214Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
Public FOXA2 analysis runs
- FOXA2 analysis run — FOXA2 (868 variants) — completed 2026-08-20