TPO (Thyroid peroxidase) variants and mutations
TPO (also known as Thyroid peroxidase) is a human protein-coding gene encoding a thyroid peroxidase protein. It oxidizes iodide and catalyzes iodination and coupling reactions on thyroglobulin that generate thyroid hormones. Biallelic loss-of-function variants cause thyroid dyshormonogenesis and congenital hypothyroidism, usually with goiter if untreated. This analysis covers 1,998 TPO variants and mutations. Of these, 48% have computational variant effect predictions. Disease context includes familial thyroid dyshormonogenesis, hyperthyroidism, and hypothyroidism. Example TPO variants include A3T, A3V, and L4P.
Variant analysis overview
- Gene: TPO
- Protein: Thyroid peroxidase
- UniProt accession: P07202
- Organism: Homo sapiens
- Variants analyzed: 1998
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 1,660 unspecified-consequence records; 1 stop retained variant; 42 synonymous variants; 245 missense variants; 16 stop-gained variants; 22 frameshift variants; 4 in-frame deletions; 1 in-frame insertions; 2 splice-region variants; 3 substitution
- Prediction scores: 951 variants have prediction scores (48% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: familial thyroid dyshormonogenesis, hyperthyroidism, hypothyroidism, congenital hypothyroidism, thyroid gland disorder, Hashimoto thyroiditis, Abnormality of the thyroid gland, nodular goiter, autoimmune disease, autoimmune thyroid disease, myxedema, nontoxic goiter.
Protein structure and variant hotspots
- Protein features: 1 transmembrane segments; 2 domains; 8 binding sites; 4 post-translational modification sites.
- Structural context: 235 variants have structural context.
- PTM context: 8 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 TPO variants
Examples include A3T, A3V, L4P, L4R, L4L, A5S, A5T, A5V. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A3T (p.Ala3Thr), rs749399164, ExAC rs749399164, gnomAD rs749399164, AlphaMissense 0.09, MetaLR 0.14, Variant assessed as somatic; moderate impact.
- A3V (p.Ala3Val), rs151268825, ClinGen CA1511258, cosmic curated COSV61101, ClinVar RCV000936416, AlphaMissense 0.10, MetaLR 0.12, Likely benign, not provided
- L4P (p.Leu4Pro), TOPMed rs1348634145, gnomAD rs1348634145
- L4R (p.Leu4Arg), TOPMed rs1348634145, gnomAD rs1348634145
- L4L (p.Leu4Leu), rs9678281, Conflicting interpretations
- A5S (p.Ala5Ser), ESP rs369441749, ExAC rs369441749, TOPMed rs369441749, gnomAD rs369441749
- A5T (p.Ala5Thr), rs369441749, cosmic curated COSV61098, ESP rs369441749, ExAC rs369441749, AlphaMissense 0.11, MetaLR 0.18, Uncertain significance, not specified
- A5V (p.Ala5Val), rs764885513, NCI-TCGA Cosmic COSV6111, cosmic curated COSV61111, ExAC rs764885513, AlphaMissense 0.10, MetaLR 0.11, Variant assessed as somatic; moderate impact.
- V6L (p.Val6Leu), cosmic curated COSV61095
- L7M (p.Leu7Met), NCI-TCGA Cosmic COSV6109, Variant assessed as somatic; moderate impact.
- S8C (p.Ser8Cys), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10022, NCI-TCGA Cosmic COSV6110, Variant assessed as somatic; moderate impact.
- S8F (p.Ser8Phe), NCI-TCGA Cosmic COSV1002, NCI-TCGA Cosmic COSV6110, cosmic curated COSV61102, Variant assessed as somatic; moderate impact.
- S8P (p.Ser8Pro), TOPMed rs1662674672, gnomAD rs1662674672
- V9A (p.Val9Ala), ExAC rs765915244, gnomAD rs765915244
- T10K (p.Thr10Lys), cosmic curated COSV10733
- T10M (p.Thr10Met), cosmic curated COSV61107, 1000Genomes rs200164576, ExAC rs200164576, TOPMed rs200164576, Uncertain significance, not specified
- L11V (p.Leu11Val), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61104, Variant assessed as somatic; moderate impact.
- V12L (p.Val12Leu), Ensembl rs1662676817
- M13I (p.Met13Ile), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10021, Variant assessed as somatic; moderate impact.
- M13T (p.Met13Thr), rs756354638, ClinGen CA1511273, ClinVar RCV004470905, ExAC rs756354638, AlphaMissense 0.13, MetaLR 0.17, Uncertain significance, Inborn genetic diseases
- M13V (p.Met13Val), ExAC rs748473380, gnomAD rs748473380
- A14V (p.Ala14Val), gnomAD rs1219185453
- C15R (p.Cys15Arg), TOPMed rs1372414235, gnomAD rs1372414235
- T16K (p.Thr16Lys), rs1259378236, ClinGen CA345727933, ClinVar RCV003241994, TOPMed rs1259378236, AlphaMissense 0.31, MetaLR 0.32, Uncertain significance, Inborn genetic diseases
- E17* (p.Glu17Ter), cosmic curated COSV10519
- E17D (p.Glu17Asp), gnomAD rs1662678923
- E17G (p.Glu17Gly), cosmic curated COSV10022, Ensembl rs1662678693
- A18D (p.Ala18Asp), ExAC rs778171761, gnomAD rs778171761
- A18P (p.Ala18Pro), cosmic curated COSV61097
- F20L (p.Phe20Leu), gnomAD rs979168390
- P21L (p.Pro21Leu), rs868461747, NCI-TCGA Cosmic COSV6110, cosmic curated COSV61103, TOPMed rs868461747, CADD 22.00, SIFT 0.14, Variant assessed as somatic; moderate impact.
- P21S (p.Pro21Ser), NCI-TCGA Cosmic COSV1002, NCI-TCGA Cosmic COSV6111, cosmic curated COSV61111, Variant assessed as somatic; moderate impact.
- P21T (p.Pro21Thr), cosmic curated COSV10022
- F22L (p.Phe22Leu), cosmic curated COSV10587, TOPMed rs1662680134
- I23F (p.Ile23Phe), TOPMed rs1237678270, gnomAD rs1237678270
- I23N (p.Ile23Asn), Ensembl rs1573078129
- I23T (p.Ile23Thr), cosmic curated COSV61113
- I23V (p.Ile23Val), TOPMed rs1237678270, gnomAD rs1237678270
- S24* (p.Ser24Ter), ExAC rs781708047, TOPMed rs781708047, gnomAD rs781708047, Likely benign
- S24L (p.Ser24Leu), rs781708047, cosmic curated COSV10733, ExAC rs781708047, TOPMed rs781708047, AlphaMissense 0.09, MetaLR 0.06, Likely benign, Inborn genetic diseases
- R25S (p.Arg25Ser), Ensembl rs1662681688
- R25T (p.Arg25Thr), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61101, Variant assessed as somatic; moderate impact.
- G26R (p.Gly26Arg), cosmic curated COSV61111, ExAC rs778914648, TOPMed rs778914648, gnomAD rs778914648, Uncertain significance, Inborn genetic diseases
- G26V (p.Gly26Val), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10022, Variant assessed as somatic; moderate impact.
- G26W (p.Gly26Trp), ExAC rs778914648, TOPMed rs778914648, gnomAD rs778914648
- K27I (p.Lys27Ile), cosmic curated COSV10587
- K27T (p.Lys27Thr), cosmic curated COSV61105, gnomAD rs1172049371
- E28* (p.Glu28Ter), cosmic curated COSV61110, CADD 20.80
- E28K (p.Glu28Lys), cosmic curated COSV61102, Ensembl rs140144373
- E28V (p.Glu28Val), ExAC rs776431852, gnomAD rs776431852
- L30F (p.Leu30Phe), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10022, CADD 23.50, PolyPhen-2 0.21, Variant assessed as somatic; moderate impact.
- L30I (p.Leu30Ile), Ensembl rs746373581
- W31L (p.Trp31Leu), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61102, Variant assessed as somatic; moderate impact.
- W31R (p.Trp31Arg), ESP rs377431227, ExAC rs377431227, TOPMed rs377431227, gnomAD rs377431227
- G32V (p.Gly32Val), gnomAD rs1247327151
- K33E (p.Lys33Glu), ESP rs138549914
- P34S (p.Pro34Ser), TOPMed rs1246123925
- P34T (p.Pro34Thr), cosmic curated COSV61104
- E35D (p.Glu35Asp), cosmic curated COSV61105, gnomAD rs866128359
- E35K (p.Glu35Lys), cosmic curated COSV61103
- E36D (p.Glu36Asp), TOPMed rs1663941317, gnomAD rs1663941317, NCI-TCGA Cosmic COSV6109, cosmic curated COSV61093, Variant assessed as somatic; moderate impact.
- E36G (p.Glu36Gly), gnomAD rs1189595740
- E36K (p.Glu36Lys), TOPMed rs960990162, gnomAD rs960990162
- S37C (p.Ser37Cys), gnomAD rs1663942050
- S37T (p.Ser37Thr), TOPMed rs1394689813, gnomAD rs1394689813
- R38C (p.Arg38Cys), NCI-TCGA Cosmic COSV6109, cosmic curated COSV61093, CADD 32.00, PolyPhen-2 1.00, Variant assessed as somatic; moderate impact.
- R38H (p.Arg38His), cosmic curated COSV61099, 1000Genomes rs200427779, ESP rs200427779, ExAC rs200427779, CADD 26.70, PolyPhen-2 0.99
- R38L (p.Arg38Leu), rs200427779, 1000Genomes rs200427779, ESP rs200427779, ExAC rs200427779, AlphaMissense 0.11, MetaLR 0.06, Variant assessed as somatic; moderate impact.
- V39A (p.Val39Ala), NCI-TCGA TCGA novel, CADD 19.20, SIFT 0.18, Variant assessed as somatic; moderate impact.
- S40Y (p.Ser40Tyr), cosmic curated COSV10021
- S41I (p.Ser41Ile), ExAC rs780233344, TOPMed rs780233344, gnomAD rs780233344
- S41N (p.Ser41Asn), ExAC rs780233344, TOPMed rs780233344, gnomAD rs780233344
- S41R (p.Ser41Arg), 1000Genomes rs572043824, ExAC rs572043824, TOPMed rs572043824, gnomAD rs572043824, Uncertain significance, Inborn genetic diseases
- V42I (p.Val42Ile), rs147325430, NCI-TCGA Cosmic COSV6109, cosmic curated COSV61098, 1000Genomes rs147325430, CADD 6.87, PolyPhen-2 0.00, Likely benign, not provided
- L43F (p.Leu43Phe), cosmic curated COSV10021
- E44G (p.Glu44Gly), gnomAD rs1663944805
- E44K (p.Glu44Lys), gnomAD rs1433653658
- E44Q (p.Glu44Gln), gnomAD rs1433653658
- E45D (p.Glu45Asp), gnomAD rs1273796212
- E45K (p.Glu45Lys), rs1558265699, NCI-TCGA Cosmic COSV6110, cosmic curated COSV61102, Ensembl rs1558265699, AlphaMissense 0.14, MetaLR 0.08, Variant assessed as somatic; moderate impact.
- E45E (p.Glu45Glu), gnomAD 3-184375587-C-T, CADD 4.17
- S46N (p.Ser46Asn), Ensembl rs1663945878
- K47R (p.Lys47Arg), Ensembl rs1663946403
- R48C (p.Arg48Cys), cosmic curated COSV61099
- R48H (p.Arg48His), NCI-TCGA Cosmic COSV6109, cosmic curated COSV61096, TOPMed rs1463924579, gnomAD rs1463924579, Variant assessed as somatic; moderate impact.
- R48L (p.Arg48Leu), TOPMed rs1463924579, gnomAD rs1463924579
- R48S (p.Arg48Ser), TOPMed rs1377098657, gnomAD rs1377098657
- L49M (p.Leu49Met), cosmic curated COSV61106
- L49P (p.Leu49Pro), ExAC rs749097257, TOPMed rs749097257, gnomAD rs749097257
- V50V (p.Val50Val), rs754197840, gnomAD 3-184375548-C-G, CADD 9.33
- V50M (p.Val50Met), gnomAD 3-184375550-C-T, CADD 25.80, PolyPhen-2 1.00
- V50I (p.Val50Ile), rs1195404124, gnomAD 3-184375586-C-T, CADD 6.26, PolyPhen-2 0.00
- V50F (p.Val50Phe), gnomAD 3-184375586-C-A, CADD 9.15, PolyPhen-2 0.02
- D51V (p.Asp51Val), TOPMed rs1558265751, SIFT 0.07
- D51N (p.Asp51Asn), rs1005731602, gnomAD 3-184373564-C-T, CADD 27.80, PolyPhen-2 0.99
- D51D (p.Asp51Asp), gnomAD 3-184375545-G-A, CADD 9.77
- T52S (p.Thr52Ser), gnomAD rs1663948816, SIFT 0.36
- A53P (p.Ala53Pro), UniProt VAR 021622, Pathogenic, in TDH2A
- A53T (p.Ala53Thr), rs199694732, NCI-TCGA Cosmic COSV6110, cosmic curated COSV61101, TOPMed rs199694732, AlphaMissense 0.18, MetaLR 0.27, Variant assessed as somatic; moderate impact., in TDH2A
- M54T (p.Met54Thr), Ensembl rs756378279
- Y55* (p.Tyr55Ter), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61101, Variant assessed as somatic; high impact.
- Y55H (p.Tyr55His), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61102, CADD 14.50, SIFT 0.00, Variant assessed as somatic; moderate impact.
- A56G (p.Ala56Gly), ExAC rs771469941, TOPMed rs771469941, gnomAD rs771469941
- A56P (p.Ala56Pro), ExAC rs745582362, gnomAD rs745582362
- A56T (p.Ala56Thr), rs745582362, NCI-TCGA Cosmic COSV6110, cosmic curated COSV61100, ExAC rs745582362, AlphaMissense 0.44, MetaLR 0.08, Variant assessed as somatic; moderate impact.
- A56V (p.Ala56Val), ExAC rs771469941, TOPMed rs771469941, gnomAD rs771469941
- T57A (p.Thr57Ala), TOPMed rs1663951571
- T57K (p.Thr57Lys), ExAC rs775202863, TOPMed rs775202863, gnomAD rs775202863
- T57M (p.Thr57Met), rs775202863, NCI-TCGA Cosmic COSV6109, cosmic curated COSV61097, ExAC rs775202863, AlphaMissense 0.30, MetaLR 0.22, Variant assessed as somatic; moderate impact.
- T57I (p.Thr57Ile), rs779250490, gnomAD 3-184375570-G-A, CADD 17.20, PolyPhen-2 0.01
- M58I (p.Met58Ile), NCI-TCGA Cosmic COSV1002, cosmic curated COSV10021, NCI-TCGA Cosmic COSV6110, cosmic curated COSV10453, Variant assessed as somatic; moderate impact.
- M58K (p.Met58Lys), TOPMed rs1663952500, SIFT 0.26
- Q59Q (p.Gln59Gln), gnomAD 3-184375596-C-T, CADD 6.57
- R60G (p.Arg60Gly), Ensembl rs2148445787
- N61I (p.Asn61Ile), cosmic curated COSV61096
- L62I (p.Leu62Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L62V (p.Leu62Val), Ensembl rs1573162392
- L62P (p.Leu62Pro), gnomAD 3-184375558-A-G, CADD 27.90, PolyPhen-2 1.00
- L62L (p.Leu62Leu), gnomAD 3-184375559-G-A, CADD 12.60
- K63M (p.Lys63Met), cosmic curated COSV99046
- K63R (p.Lys63Arg), cosmic curated COSV61104, Ensembl rs903800027
- K63T (p.Lys63Thr), cosmic curated COSV61097
- K64E (p.Lys64Glu), TOPMed rs1293186318, gnomAD rs1293186318
- K64R (p.Lys64Arg), cosmic curated COSV61102, ExAC rs778505800, gnomAD rs778505800, SIFT 0.16
- R65I (p.Arg65Ile), ExAC rs750244726, gnomAD rs750244726
- R65T (p.Arg65Thr), ExAC rs750244726, gnomAD rs750244726, SIFT 0.00
- G66E (p.Gly66Glu), NCI-TCGA Cosmic COSV6110, cosmic curated COSV61109, Variant assessed as somatic; moderate impact.
- G66R (p.Gly66Arg), cosmic curated COSV61102
- G66G (p.Gly66Gly), rs771020085, gnomAD 3-184375533-T-A, CADD 14.50
- I67V (p.Ile67Val), gnomAD rs1256237029, SIFT 0.18
- L68F (p.Leu68Phe), cosmic curated COSV10453
- L68H (p.Leu68His), rs1338916377, NCI-TCGA Cosmic COSV1002, cosmic curated COSV10022, gnomAD rs1338916377, AlphaMissense 0.15, MetaLR 0.16, Variant assessed as somatic; moderate impact.
- L68V (p.Leu68Val), rs1466586251, gnomAD 3-184375538-A-C, CADD 22.90, PolyPhen-2 0.99
- L68L (p.Leu68Leu), gnomAD 3-184375538-A-G, CADD 10.60
- S69Y (p.Ser69Tyr), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S69T (p.Ser69Thr), gnomAD 3-184375540-C-G, CADD 23.90, PolyPhen-2 0.96
- S69N (p.Ser69Asn), rs141465516, gnomAD 3-184375540-C-T, CADD 22.90, PolyPhen-2 0.98
- S69I (p.Ser69Ile), rs141465516, gnomAD 3-184375540-C-A, CADD 24.60, PolyPhen-2 1.00
- S69G (p.Ser69Gly), gnomAD 3-184375541-T-C, CADD 25.70, PolyPhen-2 0.99
- S69R (p.Ser69Arg), gnomAD 3-184375541-T-G, CADD 24.30, PolyPhen-2 1.00
- P70A (p.Pro70Ala), rs17855780, ClinGen CA1511360, ClinVar RCV001131120, ClinVar RCV001760093, AlphaMissense 0.24, MetaLR 0.35, Uncertain significance, not provided; Deficiency of iodide peroxidase
- P70S (p.Pro70Ser), 1000Genomes rs17855780, ESP rs17855780, ExAC rs17855780, TOPMed rs17855780, Uncertain significance
- P70T (p.Pro70Thr), cosmic curated COSV61103
- P70P (p.Pro70Pro), gnomAD 3-184375554-A-G, CADD 9.46
- P70L (p.Pro70Leu), gnomAD 3-184375573-G-A, CADD 22.50, PolyPhen-2 0.14
- A71A (p.Ala71Ala), gnomAD 3-184375551-A-G, CADD 11.60
- A71V (p.Ala71Val), gnomAD 3-184375552-G-A, CADD 22.50, PolyPhen-2 0.01
- A71T (p.Ala71Thr), rs1714316088, gnomAD 3-184375553-C-T, CADD 14.60, PolyPhen-2 0.01
- Q72* (p.Gln72Ter), rs200273438, ClinGen CA1511361, ClinVar RCV001329365, ESP rs200273438, AlphaMissense 0.17, MetaLR 0.16, Pathogenic
- Q72K (p.Gln72Lys), ESP rs200273438, ExAC rs200273438, TOPMed rs200273438, gnomAD rs200273438, Pathogenic
- Q72P (p.Gln72Pro), ExAC rs746701654, TOPMed rs746701654, gnomAD rs746701654
- Q72R (p.Gln72Arg), ExAC rs746701654, TOPMed rs746701654, gnomAD rs746701654, SIFT 0.00
- Q72Q (p.Gln72Gln), rs1168060886, gnomAD 3-184373565-C-T, CADD 10.30
- L73F (p.Leu73Phe), ESP rs370646349, ExAC rs370646349, TOPMed rs370646349, gnomAD rs370646349
- L73I (p.Leu73Ile), ESP rs370646349, ExAC rs370646349, TOPMed rs370646349, gnomAD rs370646349
- L73P (p.Leu73Pro), rs1478800617, ClinGen CA345729486, ClinVar RCV003141135, TOPMed rs1478800617, AlphaMissense 0.77, MetaLR 0.43, Uncertain significance, not provided
- L73V (p.Leu73Val), ESP rs370646349, ExAC rs370646349, TOPMed rs370646349, gnomAD rs370646349, SIFT 0.03
- L74V (p.Leu74Val), gnomAD rs1459801387, SIFT 0.00
- S75C (p.Ser75Cys), cosmic curated COSV61099
- S75F (p.Ser75Phe), cosmic curated COSV61097, SIFT 0.02
- S75Y (p.Ser75Tyr), NCI-TCGA Cosmic COSV6109, NCI-TCGA Cosmic COSV6111, cosmic curated COSV61113, CADD 19.30, SIFT 0.04, Variant assessed as somatic; moderate impact.
- F76L (p.Phe76Leu), gnomAD rs1190794049
- F76S (p.Phe76Ser), ExAC rs748602439, gnomAD rs748602439, SIFT 0.00
- F76F (p.Phe76Phe), rs530014873, gnomAD 3-184375542-A-G, CADD 7.05
- S77F (p.Ser77Phe), cosmic curated COSV61103
- S77P (p.Ser77Pro), Ensembl rs80193921, MetaLR 0.15, MetaSVM -0.85
- K78N (p.Lys78Asn), Ensembl rs2148490719, MetaLR 0.04, MetaSVM -1.02
- K78K (p.Lys78Lys), gnomAD 3-184373571-C-T, CADD 9.58
- L79R (p.Leu79Arg), cosmic curated COSV61105, MetaLR 0.13, MetaSVM -0.96
- L79L (p.Leu79Leu), gnomAD 3-184373535-C-T, CADD 10.10
- L79C (p.Leu79Cys), gnomAD 3-184373540-GA-G, CADD 23.40
- L79T (p.Leu79Thr), gnomAD 3-184373540-G-GT, CADD 28.40
- L79V (p.Leu79Val), rs1198282196, gnomAD 3-184373558-G-C, CADD 23.00, PolyPhen-2 0.57
- P80S (p.Pro80Ser), cosmic curated COSV10453, MetaLR 0.19, MetaSVM -0.75
- E81A (p.Glu81Ala), NCI-TCGA Cosmic COSV6110, Variant assessed as somatic; moderate impact.
- E81D (p.Glu81Asp), ExAC rs773394485, gnomAD rs773394485
- E81V (p.Glu81Val), cosmic curated COSV61107, MetaLR 0.26, MetaSVM -0.47
- E78del (p.Glu78del), gnomAD 3-184373576-TCTC-, CADD 19.80
- E81K (p.Glu81Lys), rs1264355691, gnomAD 3-184373579-C-T, CADD 21.00, PolyPhen-2 0.06
- E81E (p.Glu81Glu), rs1714144043, gnomAD 3-184373580-C-T, CADD 13.90
Public TPO analysis runs
- TPO analysis run — TPO (1,998 variants) — completed 2026-08-20