TSHR (Thyrotropin receptor) variants and mutations
TSHR (also known as Thyrotropin receptor) is a human protein-coding gene encoding a thyrotropin receptor protein. TSH signaling through this pathway drives thyroid-hormone synthesis, iodine handling, and thyroid growth. Activating variants can cause autonomous hyperthyroidism, whereas loss-of-function variants can cause TSH resistance and congenital hypothyroidism. This analysis covers 1,889 TSHR variants and mutations. Of these, 49% have computational variant effect predictions. Disease context includes hypothyroidism due to TSH receptor mutations, familial hyperthyroidism due to mutations in TSH receptor, and hypothyroidism. Example TSHR variants include M1?, R2K, and R2S.
Variant analysis overview
- Gene: TSHR
- Protein: Thyrotropin receptor
- UniProt accession: P16473
- Organism: Homo sapiens
- Variants analyzed: 1889
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,719 unspecified-consequence records; 72 missense variants; 69 synonymous variants; 16 frameshift variants; 4 in-frame deletions; 3 stop-gained variants; 3 splice-region variants; 2 stop lost; 1 substitution
- Prediction scores: 918 variants have prediction scores (49% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hypothyroidism due to TSH receptor mutations, familial hyperthyroidism due to mutations in TSH receptor, hypothyroidism, familial gestational hyperthyroidism, thyroid gland disorder, myxedema, congenital hypothyroidism, Graves disease, hereditary disease, hyperthyroidism, thyrotoxicosis, thyroid cancer.
Protein structure and variant hotspots
- Protein features: 7 transmembrane segments; 7 post-translational modification sites.
- Structural context: 390 variants have structural context.
- PTM context: 22 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, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable TSHR variants
Examples include M1?, R2K, R2S, R2W, R2G, P3L, P3Q, P3S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV99992
- R2K (p.Arg2Lys), TOPMed rs939356195, gnomAD rs939356195, REVEL 0.16, CADD 22.20
- R2S (p.Arg2Ser), ExAC rs750257586, gnomAD rs750257586, REVEL 0.32, CADD 23.30
- R2W (p.Arg2Trp), Ensembl rs1886623378
- R2G (p.Arg2Gly), gnomAD 14-80955684-A-G, REVEL 0.17, CADD 23.20
- P3L (p.Pro3Leu), cosmic curated COSV53319, gnomAD rs1263008401, REVEL 0.28, CADD 17.20
- P3Q (p.Pro3Gln), gnomAD rs1263008401, REVEL 0.15, CADD 16.40
- P3S (p.Pro3Ser), Ensembl rs2139669082
- P3P (p.Pro3Pro), gnomAD 14-80955689-G-C, CADD 7.14
- A4E (p.Ala4Glu), TOPMed rs1347451255, gnomAD rs1347451255, REVEL 0.10, CADD 0.22
- A4S (p.Ala4Ser), gnomAD rs1460409181, REVEL 0.12, CADD 0.71
- A4T (p.Ala4Thr), rs1460409181, NCI-TCGA Cosmic COSV5331, cosmic curated COSV53315, gnomAD rs1460409181, REVEL 0.11, CADD 2.73, Variant assessed as somatic; moderate impact.
- A4V (p.Ala4Val), NCI-TCGA TCGA novel, TOPMed rs1347451255, gnomAD rs1347451255, Variant assessed as somatic; moderate impact.
- A4A (p.Ala4Ala), rs377366847, gnomAD 14-80955692-G-A, CADD 6.00
- D5A (p.Asp5Ala), Ensembl rs1594883902
- D5G (p.Asp5Gly), Ensembl rs1594883902
- D5H (p.Asp5His), TOPMed rs755970622, gnomAD rs755970622, Uncertain significance
- D5N (p.Asp5Asn), cosmic curated COSV10645, TOPMed rs755970622, gnomAD rs755970622, REVEL 0.06, CADD 1.79, Uncertain significance, Inborn genetic diseases
- D5V (p.Asp5Val), Ensembl rs1594883902
- L6F (p.Leu6Phe), NCI-TCGA Cosmic COSV5332, cosmic curated COSV53320, NCI-TCGA Cosmic COSV5333, cosmic curated COSV53333, REVEL 0.34, CADD 21.40, Variant assessed as somatic; moderate impact.
- L6L (p.Leu6Leu), rs2139669162, gnomAD 14-80955698-G-A, CADD 8.42
- Q8* (p.Gln8Ter), rs1886625440, ClinGen CA390770465, ClinVar RCV003580598, Ensembl rs1886625440, Pathogenic
- Q8H (p.Gln8His), rs773584994, gnomAD 14-80955699-C-CTG, CADD 25.10
- Q8E (p.Gln8Glu), gnomAD 14-80955702-C-G, REVEL 0.20, CADD 16.10
- L9P (p.Leu9Pro), TOPMed rs1235510229, gnomAD rs1235510229, REVEL 0.58, CADD 26.00
- L9L (p.Leu9Leu), gnomAD 14-80955707-G-A, CADD 3.74
- V10E (p.Val10Glu), ExAC rs766480234, gnomAD rs766480234, REVEL 0.39, CADD 4.98
- V10G (p.Val10Gly), ExAC rs766480234, gnomAD rs766480234
- V10M (p.Val10Met), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- V10V (p.Val10Val), rs1331795234, gnomAD 14-80955710-G-T, CADD 3.60
- L11L (p.Leu11Leu), rs1566735288, gnomAD 14-80955713-G-A, CADD 8.67
- L12L (p.Leu12Leu), rs1409710392, gnomAD 14-80955716-G-A, CADD 7.46
- L13F (p.Leu13Phe), Ensembl rs2139669314, REVEL 0.31, CADD 23.90
- L13A (p.Leu13Ala), rs1318223887, gnomAD 14-80955714-C-CT, CADD 24.40
- L13L (p.Leu13Leu), gnomAD 14-80955719-C-A, CADD 2.54
- D14E (p.Asp14Glu), ExAC rs754574062, gnomAD rs754574062, cosmic curated COSV53326, REVEL 0.20, CADD 14.60
- D14G (p.Asp14Gly), TOPMed rs1398718031
- D14H (p.Asp14His), TOPMed rs1886628490, REVEL 0.14, CADD 7.80
- D14N (p.Asp14Asn), NCI-TCGA Cosmic COSV9999, cosmic curated COSV99992, Variant assessed as somatic; moderate impact.
- D14V (p.Asp14Val), TOPMed rs1398718031
- D14Y (p.Asp14Tyr), TOPMed rs1886628490
- P16S (p.Pro16Ser), cosmic curated COSV53317
- P16T (p.Pro16Thr), ExAC rs778660440, gnomAD rs778660440, REVEL 0.12, CADD 10.30
- p.Pro16 Leu19del, gnomAD 14-80955719-CGACC, CADD 16.80
- P16H (p.Pro16His), gnomAD 14-80955727-C-A, REVEL 0.26, CADD 15.80
- R17G (p.Arg17Gly), gnomAD rs1470956073, REVEL 0.14, CADD 3.68
- R17K (p.Arg17Lys), TOPMed rs1334550660, gnomAD rs1334550660, REVEL 0.20, CADD 16.40
- R17T (p.Arg17Thr), TOPMed rs1334550660, gnomAD rs1334550660
- R17S (p.Arg17Ser), gnomAD 14-80955731-G-T, REVEL 0.13, CADD 7.21
- R17R (p.Arg17Arg), rs147305381, gnomAD 14-80955731-G-A, CADD 5.88
- D18E (p.Asp18Glu), Ensembl rs2139669436, REVEL 0.14, CADD 8.79
- D18N (p.Asp18Asn), ExAC rs758625628, gnomAD rs758625628, REVEL 0.07, CADD 5.17
- D18Y (p.Asp18Tyr), cosmic curated COSV10610, ExAC rs758625628, gnomAD rs758625628, REVEL 0.14, CADD 13.90
- D18D (p.Asp18Asp), rs2139669436, gnomAD 14-80955734-C-T, CADD 7.58
- L19M (p.Leu19Met), TOPMed rs1299194076
- L19P (p.Leu19Pro), TOPMed rs1296628682, gnomAD rs1296628682, REVEL 0.20, CADD 16.20
- L19L (p.Leu19Leu), gnomAD 14-80955735-C-T, CADD 8.18
- L19Q (p.Leu19Gln), gnomAD 14-80955736-T-A, REVEL 0.46, CADD 15.80
- G20D (p.Gly20Asp), Ensembl rs2139669485, REVEL 0.19, CADD 13.80
- G20S (p.Gly20Ser), cosmic curated COSV10814, REVEL 0.19, CADD 1.33
- G21E (p.Gly21Glu), cosmic curated COSV53335
- G21R (p.Gly21Arg), TOPMed rs1006500286, gnomAD rs1006500286, REVEL 0.31, CADD 22.80
- M22R (p.Met22Arg), 1000Genomes rs562487889, ExAC rs562487889, TOPMed rs562487889, gnomAD rs562487889
- M22T (p.Met22Thr), 1000Genomes rs562487889, ExAC rs562487889, TOPMed rs562487889, gnomAD rs562487889, REVEL 0.06, CADD 2.54
- M22I (p.Met22Ile), gnomAD 14-80955746-G-A, REVEL 0.11, CADD 9.96
- G23E (p.Gly23Glu), Ensembl rs2139669562
- G23R (p.Gly23Arg), TOPMed rs1886632792, REVEL 0.05, CADD 16.30
- G23V (p.Gly23Val), cosmic curated COSV53324
- G23G (p.Gly23Gly), gnomAD 14-80955749-G-T, CADD 6.95
- C24F (p.Cys24Phe), cosmic curated COSV53327
- C24G (p.Cys24Gly), Ensembl rs1594884072
- C24Y (p.Cys24Tyr), Ensembl rs2139669591
- C24C (p.Cys24Cys), gnomAD 14-80955752-T-C, CADD 6.68
- S25L (p.Ser25Leu), NCI-TCGA Cosmic COSV5331, cosmic curated COSV53315, TOPMed rs1279964862, gnomAD rs1279964862, Variant assessed as somatic; moderate impact.
- S25P (p.Ser25Pro), TOPMed rs1886633581, REVEL 0.06, CADD 3.60
- S25W (p.Ser25Trp), TOPMed rs1279964862, gnomAD rs1279964862, REVEL 0.24, CADD 13.50
- S25S (p.Ser25Ser), rs747394165, gnomAD 14-80955755-G-A, CADD 0.63
- S26S (p.Ser26Ser), rs1017867335, gnomAD 14-80955758-T-C, CADD 8.19
- P27L (p.Pro27Leu), 1000Genomes rs532920088, ExAC rs532920088, gnomAD rs532920088, REVEL 0.23, CADD 9.66
- P27R (p.Pro27Arg), cosmic curated COSV53317
- P27P (p.Pro27Pro), gnomAD 14-80955761-A-G, CADD 6.68
- P28L (p.Pro28Leu), Ensembl rs1886634720, REVEL 0.17, CADD 18.70
- P28S (p.Pro28Ser), gnomAD rs1253500374, REVEL 0.07, CADD 14.40
- C29* (p.Cys29Ter), rs777166186, ClinGen CA390770595, ClinVar RCV003731096, ExAC rs777166186, CADD 32.00, Pathogenic
- C29S (p.Cys29Ser), cosmic curated COSV53316
- C29W (p.Cys29Trp), rs777166186, ClinGen CA7293984, ClinVar RCV002988107, ClinVar RCV003491298, REVEL 0.58, CADD 21.30, Uncertain significance, not provided; Inborn genetic diseases
- E30D (p.Glu30Asp), cosmic curated COSV99991, REVEL 0.15, CADD 16.30
- E30K (p.Glu30Lys), NCI-TCGA Cosmic COSV5331, cosmic curated COSV53315, REVEL 0.28, CADD 20.40, Variant assessed as somatic; moderate impact.
- E30Q (p.Glu30Gln), cosmic curated COSV10514
- E30* (p.Glu30Ter), gnomAD 14-80955768-G-T, CADD 34.00
- E30G (p.Glu30Gly), gnomAD 14-80955769-A-G, REVEL 0.36, CADD 24.00
- E30E (p.Glu30Glu), rs1198068309, gnomAD 14-80955770-G-A, CADD 10.10
- C31* (p.Cys31Ter), rs745922510, ExAC rs745922510, gnomAD rs745922510, CADD 35.00, Likely benign
- C31R (p.Cys31Arg), cosmic curated COSV53331
- C31Y (p.Cys31Tyr), Ensembl rs2139669712
- C31C (p.Cys31Cys), rs745922510, gnomAD 14-80955773-C-T, CADD 12.70
- H32L (p.His32Leu), cosmic curated COSV53335
- H32Y (p.His32Tyr), ExAC rs769881177, TOPMed rs769881177, gnomAD rs769881177, REVEL 0.14, CADD 17.50, Uncertain significance, Inborn genetic diseases
- H32R (p.His32Arg), gnomAD 14-80955775-A-G, REVEL 0.07, CADD 15.40
- Q33E (p.Gln33Glu), Ensembl rs2139669748
- Q33R (p.Gln33Arg), gnomAD rs1886635842, REVEL 0.14, CADD 22.00
- Q33* (p.Gln33Ter), gnomAD 14-80955777-C-T, CADD 36.00
- E34D (p.Glu34Asp), cosmic curated COSV53329
- E34K (p.Glu34Lys), rs45499704, ClinGen CA7293987, ClinVar RCV001118136, ClinVar RCV001118137, REVEL 0.39, CADD 22.40, Conflicting interpretations, Inborn genetic diseases; not specified; Hypothyroidism due to TSH receptor mutat
- E34V (p.Glu34Val), gnomAD rs1418754419, REVEL 0.26, CADD 23.30
- E35K (p.Glu35Lys), rs1192804611, NCI-TCGA Cosmic COSV5332, cosmic curated COSV53327, TOPMed rs1192804611, REVEL 0.19, CADD 21.30, Variant assessed as somatic; moderate impact.
- E35E (p.Glu35Glu), gnomAD 14-80955785-G-A, CADD 10.00
- D36H (p.Asp36His), rs61747482, ClinGen CA118191, cosmic curated COSV99035, ClinVar RCV000122245, REVEL 0.28, CADD 23.70, Benign/Likely benign, not specified; not provided; Familial hyperthyroidism due to mutations in TSH re
- D36D (p.Asp36Asp), rs767158566, gnomAD 14-80955788-C-T, CADD 14.40
- F37L (p.Phe37Leu), Ensembl rs2139669840
- R38K (p.Arg38Lys), cosmic curated COSV10514
- R38T (p.Arg38Thr), cosmic curated COSV53330
- R38G (p.Arg38Gly), gnomAD 14-80955792-A-G, REVEL 0.55, CADD 24.80
- V39L (p.Val39Leu), Ensembl rs2139669849
- V39D (p.Val39Asp), gnomAD 14-80955796-T-A, REVEL 0.68, CADD 30.00
- T40I (p.Thr40Ile), ExAC rs773044895, TOPMed rs773044895, gnomAD rs773044895, REVEL 0.56, CADD 24.10
- T40N (p.Thr40Asn), cosmic curated COSV10883
- T40S (p.Thr40Ser), ExAC rs773044895, TOPMed rs773044895, gnomAD rs773044895
- C41R (p.Cys41Arg), gnomAD rs1410738370, REVEL 0.69, CADD 26.00
- C41S (p.Cys41Ser), rs121908869, ClinGen CA118227, ClinVar RCV000006812, ClinVar RCV000415318, REVEL 0.74, CADD 24.80, Conflicting interpretations, not specified; not provided; Familial hyperthyroidism due to mutations in TSH re
- C41W (p.Cys41Trp), Ensembl rs2139669901
- C41Y (p.Cys41Tyr), ESP rs121908869, ExAC rs121908869, TOPMed rs121908869, gnomAD rs121908869, Pathogenic, in CHNG1
- K42* (p.Lys42Ter), ExAC rs766387143, TOPMed rs766387143, gnomAD rs766387143, CADD 39.00
- K42E (p.Lys42Glu), rs766387143, ExAC rs766387143, TOPMed rs766387143, gnomAD rs766387143, REVEL 0.42, CADD 22.80, Variant assessed as somatic; moderate impact.
- K42R (p.Lys42Arg), gnomAD 14-80955805-A-G, REVEL 0.19, CADD 22.40
- K42K (p.Lys42Lys), gnomAD 14-80955806-G-A, CADD 13.40
- D43H (p.Asp43His), gnomAD rs1886638900, REVEL 0.36, CADD 27.30
- D43N (p.Asp43Asn), NCI-TCGA Cosmic COSV5332, cosmic curated COSV53323, gnomAD rs1886638900, REVEL 0.17, CADD 23.30, Variant assessed as somatic; moderate impact.
- D43Y (p.Asp43Tyr), gnomAD 14-80955807-G-T, REVEL 0.48, CADD 28.30
- I44M (p.Ile44Met), rs984401719, gnomAD rs984401719, REVEL 0.18, CADD 11.80, Variant assessed as somatic; moderate impact.
- I44S (p.Ile44Ser), TOPMed rs1886639507, REVEL 0.50, CADD 24.60
- I44V (p.Ile44Val), gnomAD rs1438707214, REVEL 0.14, CADD 11.10
- Q45H (p.Gln45His), Ensembl rs2139669967
- Q45R (p.Gln45Arg), rs2503157070, ClinGen CA390770705, ClinVar RCV004476483, Uncertain significance, Inborn genetic diseases
- R46C (p.Arg46Cys), rs1276734165, NCI-TCGA Cosmic COSV5332, cosmic curated COSV53322, TOPMed rs1276734165, REVEL 0.39, CADD 19.20, Variant assessed as somatic; moderate impact.
- R46G (p.Arg46Gly), TOPMed rs1276734165, gnomAD rs1276734165, REVEL 0.29, CADD 14.40
- R46H (p.Arg46His), NCI-TCGA Cosmic COSV5332, cosmic curated COSV53324, Ensembl rs2139669985, REVEL 0.14, CADD 16.00, Variant assessed as somatic; moderate impact.
- R46L (p.Arg46Leu), gnomAD 14-80955817-G-T, REVEL 0.16, CADD 14.80
- R46P (p.Arg46Pro), gnomAD 14-80955817-G-C, REVEL 0.52, CADD 17.10
- I47I (p.Ile47Ile), rs1566735446, gnomAD 14-80955821-C-T, CADD 14.00
- P48S (p.Pro48Ser), ExAC rs754498150, gnomAD rs754498150, REVEL 0.40, CADD 23.70
- S49C (p.Ser49Cys), cosmic curated COSV53315, REVEL 0.21, CADD 23.50
- S49G (p.Ser49Gly), rs147137913, ClinGen CA162625, cosmic curated COSV10731, ClinVar RCV000122243, REVEL 0.10, CADD 20.10, Conflicting interpretations, not provided
- S49N (p.Ser49Asn), cosmic curated COSV99991
- S49T (p.Ser49Thr), Ensembl rs2139670053
- S49K (p.Ser49Lys), gnomAD 14-80955824-C-CA, CADD 25.90
- L50L (p.Leu50Leu), gnomAD 14-80955828-T-C, CADD 9.74
- P51A (p.Pro51Ala), ExAC rs752234113, gnomAD rs752234113, REVEL 0.44, CADD 24.50
- P51L (p.Pro51Leu), cosmic curated COSV53318, ExAC rs758059665, TOPMed rs758059665, gnomAD rs758059665, REVEL 0.46, CADD 24.20
- P51R (p.Pro51Arg), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- P51S (p.Pro51Ser), ExAC rs752234113, gnomAD rs752234113, REVEL 0.47, CADD 24.90
- P51P (p.Pro51Pro), rs777358636, gnomAD 14-80955833-G-A, CADD 6.79
- P52A (p.Pro52Ala), 1000Genomes rs2234919, ESP rs2234919, ExAC rs2234919, TOPMed rs2234919, REVEL 0.09, CADD 5.88, Benign, does not contribute to the genetic susceptibility to Graves disease
- P52H (p.Pro52His), cosmic curated COSV99991
- P52L (p.Pro52Leu), NCI-TCGA Cosmic COSV9999, cosmic curated COSV99991, REVEL 0.03, CADD 19.60, Variant assessed as somatic; moderate impact., does not contribute to the genetic susceptibility to Graves disease
- P52T (p.Pro52Thr), rs2234919, ClinGen CA248749, cosmic curated COSV53318, ClinVar RCV000122244, REVEL 0.04, CADD 8.62, Benign/Likely benign, not specified; not provided; Familial hyperthyroidism due to mutations in TSH re
- S53G (p.Ser53Gly), TOPMed rs886050853, gnomAD rs886050853, Uncertain significance
- S53I (p.Ser53Ile), NCI-TCGA Cosmic COSV9999, Variant assessed as somatic; moderate impact.
- S53N (p.Ser53Asn), NCI-TCGA Cosmic COSV9999, cosmic curated COSV99992, REVEL 0.10, CADD 15.80, Variant assessed as somatic; moderate impact.
- S53R (p.Ser53Arg), Ensembl rs2139670141, REVEL 0.06, CADD 17.80, Uncertain significance, Hypothyroidism due to TSH receptor mutations; Familial hyperthyroidism due to mu
- S53T (p.Ser53Thr), gnomAD 14-80955838-G-C, REVEL 0.06, CADD 19.30
- S53S (p.Ser53Ser), gnomAD 14-80955839-T-C, CADD 7.65
- T54A (p.Thr54Ala), gnomAD rs1198983165, REVEL 0.17, CADD 21.30
- T54M (p.Thr54Met), cosmic curated COSV53329, TOPMed rs1241423317, gnomAD rs1241423317, REVEL 0.20, CADD 25.00
- T54P (p.Thr54Pro), gnomAD rs1198983165, REVEL 0.26, CADD 25.60
- T54R (p.Thr54Arg), gnomAD 14-80955841-C-G, REVEL 0.26, CADD 23.70
- T54T (p.Thr54Thr), rs2139670172, gnomAD 14-80955842-G-A, CADD 0.84
- Q55* (p.Gln55Ter), Ensembl rs2139670189
- Q55H (p.Gln55His), TOPMed rs1886642331, REVEL 0.12, CADD 20.20
- Q55R (p.Gln55Arg), gnomAD 14-80955844-A-G, REVEL 0.04, CADD 18.20
- T56I (p.Thr56Ile), rs781625203, ClinGen CA7293998, ClinVar RCV001758481, ExAC rs781625203, REVEL 0.41, CADD 17.80, Uncertain significance, not provided
- T56S (p.Thr56Ser), ExAC rs781625203, TOPMed rs781625203, gnomAD rs781625203, Uncertain significance
- T56A (p.Thr56Ala), gnomAD 14-80955846-A-G, REVEL 0.33, CADD 19.60
- T56T (p.Thr56Thr), rs1390619232, gnomAD 14-80955848-T-A, CADD 1.01
- L57M (p.Leu57Met), cosmic curated COSV10942
- L57P (p.Leu57Pro), rs200401152, ClinGen CA7293999, ClinVar RCV001763006, ClinVar RCV002496076, REVEL 0.78, CADD 31.00, Uncertain significance, Familial gestational hyperthyroidism; Hypothyroidism due to TSH receptor mutatio
- L57E (p.Leu57Glu), rs766597914, gnomAD 14-80955846-ACT-A, CADD 24.40
- L57L (p.Leu57Leu), rs1566735516, gnomAD 14-80955849-C-T, CADD 9.28
- L57R (p.Leu57Arg), gnomAD 14-80955850-T-G, REVEL 0.73, CADD 23.50
- K58R (p.Lys58Arg), Ensembl rs1566787417
Public TSHR analysis runs
- TSHR analysis run — TSHR (1,889 variants) — completed 2026-08-18