ESR1 (Estrogen receptor) variants and mutations
ESR1 (also known as Estrogen receptor) is a human protein-coding gene encoding an estrogen receptor protein. Estrogen binding redirects its transcriptional activity toward programs controlling reproductive, skeletal, metabolic, and mammary physiology. Persistent ESR1 signaling drives most hormone-receptor-positive breast cancers, while acquired activating variants are an important mechanism of endocrine-therapy resistance. This analysis covers 2,664 ESR1 variants and mutations. Of these, 33% have computational variant effect predictions. Disease context includes breast cancer, breast carcinoma, and osteoporosis. Example ESR1 variants include M1?, T2A, and T2N.
Variant analysis overview
- Gene: ESR1
- Protein: Estrogen receptor
- UniProt accession: P03372
- Organism: Homo sapiens
- Variants analyzed: 2664
- Variant scope: all variants
- Completed: 2026-08-10
Variant and mutation evidence
- Variant composition: 2,382 unspecified-consequence records; 149 missense variants; 107 synonymous variants; 5 in-frame deletions; 8 frameshift variants; 9 stop-gained variants; 1 in-frame insertions; 2 splice-region variants; 1 substitution
- Prediction scores: 888 variants have prediction scores (33% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: breast cancer, breast carcinoma, osteoporosis, endometriosis, breast neoplasm, neoplasm, Estrogen resistance syndrome, acne, hypogonadism, menopause, Premature ovarian insufficiency, polycystic ovary syndrome.
Protein structure and variant hotspots
- Protein features: 1 domains; 3 binding sites; 7 post-translational modification sites.
- Structural context: 1,002 variants have structural context.
- PTM context: 33 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 ESR1 variants
Examples include M1?, T2A, T2N, T2S, M3I, M3T, M3V, M3L. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV52790
- T2A (p.Thr2Ala), Ensembl rs2128155148, REVEL 0.41, MetaLR 0.74
- T2N (p.Thr2Asn), Ensembl rs2128155155
- T2S (p.Thr2Ser), Ensembl rs2128155148
- M3I (p.Met3Ile), TOPMed rs1778144292, gnomAD rs1778144292, REVEL 0.62, MetaLR 0.84
- M3T (p.Met3Thr), 1000Genomes rs559940774, ExAC rs559940774, TOPMed rs559940774, gnomAD rs559940774, REVEL 0.63, MetaLR 0.84
- M3V (p.Met3Val), TOPMed rs912640670, gnomAD rs912640670, REVEL 0.60, MetaLR 0.79
- M3L (p.Met3Leu), gnomAD 6-151807919-A-T, REVEL 0.63, MetaLR 0.81
- T4A (p.Thr4Ala), cosmic curated COSV52789, Ensembl rs2128155190
- T4N (p.Thr4Asn), Ensembl rs2128155194, REVEL 0.46, MetaLR 0.82
- T4S (p.Thr4Ser), Ensembl rs2128155190
- L5I (p.Leu5Ile), cosmic curated COSV10585, Ensembl rs2128155205
- L5P (p.Leu5Pro), cosmic curated COSV10802
- H6L (p.His6Leu), Ensembl rs2128155221
- H6P (p.His6Pro), Ensembl rs2128155221
- H6R (p.His6Arg), Ensembl rs2128155221
- H6Y (p.His6Tyr), rs139960913, ClinGen CA4052073, cosmic curated COSV52793, ClinVar RCV000884714, REVEL 0.49, MetaLR 0.87, Conflicting interpretations, not provided
- T7S (p.Thr7Ser), TOPMed rs1264713099, gnomAD rs1264713099
- K8* (p.Lys8Ter), Ensembl rs2128155240
- K8T (p.Lys8Thr), Ensembl rs2128155244
- K8E (p.Lys8Glu), gnomAD 6-151807934-A-G, REVEL 0.62, MetaLR 0.83
- A9E (p.Ala9Glu), Ensembl rs2128155259
- A9P (p.Ala9Pro), TOPMed rs1459388709, REVEL 0.34, MetaLR 0.52
- A9T (p.Ala9Thr), NCI-TCGA Cosmic COSV5278, cosmic curated COSV52781, TOPMed rs1459388709, Variant assessed as somatic; moderate impact.
- A9V (p.Ala9Val), Ensembl rs2128155259
- S10C (p.Ser10Cys), NCI-TCGA Cosmic COSV5280, cosmic curated COSV52804, Variant assessed as somatic; moderate impact.
- S10F (p.Ser10Phe), rs1778145541, ClinGen CA366211456, ClinVar RCV003313662, Ensembl rs1778145541, AlphaMissense 0.55, MetaLR 0.78, Uncertain significance, not provided
- S10Y (p.Ser10Tyr), gnomAD 6-151807941-C-A, REVEL 0.51, MetaLR 0.83
- S10S (p.Ser10Ser), rs2077647, gnomAD 6-151807942-T-A, CADD 8.18
- G11E (p.Gly11Glu), cosmic curated COSV10722
- G11R (p.Gly11Arg), cosmic curated COSV10722
- G11W (p.Gly11Trp), cosmic curated COSV10585
- G11V (p.Gly11Val), gnomAD 6-151807944-G-T, REVEL 0.69, MetaLR 0.88
- G11G (p.Gly11Gly), gnomAD 6-151807945-G-A, CADD 8.55
- M12I (p.Met12Ile), Ensembl rs1778146502
- M12L (p.Met12Leu), Ensembl rs2128155287, REVEL 0.16, MetaLR 0.24
- A13D (p.Ala13Asp), ExAC rs767166523, gnomAD rs767166523
- A13G (p.Ala13Gly), ExAC rs767166523, gnomAD rs767166523
- A13P (p.Ala13Pro), ExAC rs761420991, TOPMed rs761420991, gnomAD rs761420991
- A13T (p.Ala13Thr), cosmic curated COSV52802, ExAC rs761420991, TOPMed rs761420991, gnomAD rs761420991, REVEL 0.19, MetaLR 0.53
- A13V (p.Ala13Val), cosmic curated COSV10940, ExAC rs767166523, gnomAD rs767166523, REVEL 0.38, MetaLR 0.77
- A13A (p.Ala13Ala), rs1474043222, gnomAD 6-151807951-C-T, CADD 12.20
- L14I (p.Leu14Ile), Ensembl rs2128155315
- L14P (p.Leu14Pro), ESP rs369520220, ExAC rs369520220, TOPMed rs369520220, gnomAD rs369520220, REVEL 0.61, MetaLR 0.87
- L14Q (p.Leu14Gln), ESP rs369520220, ExAC rs369520220, TOPMed rs369520220, gnomAD rs369520220
- L14L (p.Leu14Leu), rs2128155315, gnomAD 6-151807952-C-T, CADD 8.42
- L15M (p.Leu15Met), Ensembl rs2128155341
- L15P (p.Leu15Pro), ExAC rs760503206, gnomAD rs760503206, REVEL 0.81, MetaLR 0.88
- L15V (p.Leu15Val), cosmic curated COSV52789
- L15L (p.Leu15Leu), rs1420549682, gnomAD 6-151807957-G-C, CADD 11.90
- H16D (p.His16Asp), Ensembl rs2128155355
- H16L (p.His16Leu), Ensembl rs2128155363
- H16N (p.His16Asn), Ensembl rs2128155355
- H16P (p.His16Pro), gnomAD 6-151807959-A-C, REVEL 0.76, MetaLR 0.84
- Q17* (p.Gln17Ter), Ensembl rs2128155367
- Q17H (p.Gln17His), Ensembl rs2128155383, NCI-TCGA Cosmic COSV9924, cosmic curated COSV99240, Variant assessed as somatic; moderate impact.
- Q17K (p.Gln17Lys), Ensembl rs2128155367
- Q17L (p.Gln17Leu), Ensembl rs2128155375
- Q17R (p.Gln17Arg), Ensembl rs2128155375
- Q17E (p.Gln17Glu), gnomAD 6-151807961-C-G, REVEL 0.52, MetaLR 0.87
- I18F (p.Ile18Phe), Ensembl rs2128155389
- I18M (p.Ile18Met), ExAC rs766314434, TOPMed rs766314434, gnomAD rs766314434
- I18V (p.Ile18Val), Ensembl rs2128155389
- I18T (p.Ile18Thr), gnomAD 6-151807965-T-C, REVEL 0.68, MetaLR 0.86
- I18I (p.Ile18Ile), rs766314434, gnomAD 6-151807966-C-A, CADD 14.00
- Q19* (p.Gln19Ter), Ensembl rs2128155408
- Q19H (p.Gln19His), ExAC rs753706485, gnomAD rs753706485
- Q19K (p.Gln19Lys), Ensembl rs2128155408
- Q19L (p.Gln19Leu), Ensembl rs2128155417
- Q19Q (p.Gln19Gln), rs753706485, gnomAD 6-151807969-A-G, CADD 12.50
- G20A (p.Gly20Ala), Ensembl rs1778148966
- G20E (p.Gly20Glu), cosmic curated COSV10722, Ensembl rs1778148966, REVEL 0.35, MetaLR 0.81
- G20R (p.Gly20Arg), Ensembl rs2128155434
- G20V (p.Gly20Val), Ensembl rs1778148966, REVEL 0.42, MetaLR 0.80
- G20W (p.Gly20Trp), Ensembl rs2128155434
- G20G (p.Gly20Gly), gnomAD 6-151807972-G-A, CADD 10.00
- N21D (p.Asn21Asp), TOPMed rs1778149215, gnomAD rs1778149215, REVEL 0.12, MetaLR 0.45
- N21K (p.Asn21Lys), ExAC rs759639731, TOPMed rs759639731, REVEL 0.13, MetaLR 0.51
- N21S (p.Asn21Ser), Ensembl rs2128155455
- N21T (p.Asn21Thr), Ensembl rs2128155455
- N21Y (p.Asn21Tyr), TOPMed rs1778149215, gnomAD rs1778149215
- N21N (p.Asn21Asn), rs759639731, gnomAD 6-151807975-C-T, CADD 10.80
- E22A (p.Glu22Ala), TOPMed rs1778150080
- E22D (p.Glu22Asp), Ensembl rs2128155478
- E22K (p.Glu22Lys), cosmic curated COSV10722, TOPMed rs1583384537, gnomAD rs1583384537, REVEL 0.60, MetaLR 0.88
- E22Q (p.Glu22Gln), TOPMed rs1583384537, gnomAD rs1583384537
- E22V (p.Glu22Val), TOPMed rs1778150080
- E22E (p.Glu22Glu), rs2128155478, gnomAD 6-151807978-G-A, CADD 13.70
- L23V (p.Leu23Val), TOPMed rs1399427744, gnomAD rs1399427744, REVEL 0.58, MetaLR 0.90
- L23L (p.Leu23Leu), rs1399427744, gnomAD 6-151807979-C-T, CADD 14.10
- E24* (p.Glu24Ter), gnomAD rs1778150690
- E24G (p.Glu24Gly), Ensembl rs2128155503
- E24K (p.Glu24Lys), gnomAD rs1778150690
- E24Q (p.Glu24Gln), gnomAD rs1778150690, REVEL 0.66, MetaLR 0.87
- E24V (p.Glu24Val), Ensembl rs2128155503
- P25L (p.Pro25Leu), Ensembl rs2128155515
- P25S (p.Pro25Ser), gnomAD rs1778150943, REVEL 0.12, MetaLR 0.28
- P25T (p.Pro25Thr), cosmic curated COSV52787, gnomAD rs1778150943
- P25A (p.Pro25Ala), gnomAD 6-151807985-C-G, REVEL 0.11, MetaLR 0.36
- P25P (p.Pro25Pro), rs2128155519, gnomAD 6-151807987-C-T, CADD 13.40
- L26M (p.Leu26Met), cosmic curated COSV52800, Ensembl rs2128155526
- L26P (p.Leu26Pro), Ensembl rs2128155534
- L26Q (p.Leu26Gln), Ensembl rs2128155534
- L26L (p.Leu26Leu), rs931122520, gnomAD 6-151807990-G-T, CADD 10.10
- N27D (p.Asn27Asp), Ensembl rs2128155547
- N27H (p.Asn27His), Ensembl rs2128155547
- N27I (p.Asn27Ile), Ensembl rs2128155552
- N27S (p.Asn27Ser), cosmic curated COSV99065, Ensembl rs2128155552
- N27T (p.Asn27Thr), Ensembl rs2128155552
- N27Y (p.Asn27Tyr), Ensembl rs2128155547
- N27N (p.Asn27Asn), rs146774945, gnomAD 6-151807993-C-T, CADD 11.20
- R28C (p.Arg28Cys), gnomAD rs1341033484, REVEL 0.60, MetaLR 0.79
- R28H (p.Arg28His), cosmic curated COSV52789, Ensembl rs2128155569, REVEL 0.37, MetaLR 0.45
- R28P (p.Arg28Pro), Ensembl rs2128155569, REVEL 0.55, MetaLR 0.65
- R28S (p.Arg28Ser), gnomAD 6-151807994-C-A, REVEL 0.41, MetaLR 0.71
- P29A (p.Pro29Ala), Ensembl rs2128155577, REVEL 0.31, MetaLR 0.52
- P29L (p.Pro29Leu), NCI-TCGA Cosmic COSV5278, TOPMed rs1778151918, gnomAD rs1778151918, REVEL 0.56, MetaLR 0.74, Variant assessed as somatic; moderate impact.
- P29Q (p.Pro29Gln), cosmic curated COSV52786, TOPMed rs1778151918, gnomAD rs1778151918, REVEL 0.32, MetaLR 0.59
- P29R (p.Pro29Arg), TOPMed rs1778151918, gnomAD rs1778151918, REVEL 0.66, MetaLR 0.78
- P29S (p.Pro29Ser), Ensembl rs2128155577, REVEL 0.23, MetaLR 0.49
- Q30* (p.Gln30Ter), Ensembl rs2128155604
- Q30H (p.Gln30His), TOPMed rs1246892882, gnomAD rs1246892882
- Q30K (p.Gln30Lys), Ensembl rs2128155604
- Q30L (p.Gln30Leu), Ensembl rs2128155613
- Q30R (p.Gln30Arg), Ensembl rs2128155613
- Q30E (p.Gln30Glu), gnomAD 6-151808000-C-G, REVEL 0.45, MetaLR 0.76
- Q30Q (p.Gln30Gln), rs1246892882, gnomAD 6-151808002-G-A, CADD 13.40
- L31F (p.Leu31Phe), cosmic curated COSV10585, Ensembl rs2128155624
- L31H (p.Leu31His), ExAC rs752794477, gnomAD rs752794477
- L31I (p.Leu31Ile), Ensembl rs2128155624
- L31P (p.Leu31Pro), cosmic curated COSV52800, ExAC rs752794477, gnomAD rs752794477, REVEL 0.69, MetaLR 0.83
- L31L (p.Leu31Leu), rs1358381466, gnomAD 6-151808005-C-G, CADD 14.20
- K32* (p.Lys32Ter), Ensembl rs2128155639
- K32M (p.Lys32Met), Ensembl rs2128155644
- K32N (p.Lys32Asn), ExAC rs200924028, gnomAD rs200924028, REVEL 0.53, MetaLR 0.86
- K32Q (p.Lys32Gln), cosmic curated COSV52781
- K32R (p.Lys32Arg), Ensembl rs2128155644
- I33F (p.Ile33Phe), Ensembl rs2128155654
- I33L (p.Ile33Leu), Ensembl rs2128155654
- I33M (p.Ile33Met), 1000Genomes rs562174818, ExAC rs562174818, TOPMed rs562174818, gnomAD rs562174818, REVEL 0.19, MetaLR 0.38
- I33T (p.Ile33Thr), Ensembl rs2128155658, REVEL 0.44, MetaLR 0.70
- I33V (p.Ile33Val), Ensembl rs2128155654
- I33I (p.Ile33Ile), rs562174818, gnomAD 6-151808011-C-T, CADD 14.30
- P34A (p.Pro34Ala), Ensembl rs1583384726, REVEL 0.53, MetaLR 0.80
- P34H (p.Pro34His), TOPMed rs1368974256
- P34L (p.Pro34Leu), TOPMed rs1368974256, REVEL 0.73, MetaLR 0.84
- P34S (p.Pro34Ser), Ensembl rs1583384726
- P34P (p.Pro34Pro), rs751886427, gnomAD 6-151808014-C-G, CADD 14.50
- L35M (p.Leu35Met), cosmic curated COSV99239, ExAC rs201899558, TOPMed rs201899558, gnomAD rs201899558, REVEL 0.40, MetaLR 0.73
- L35P (p.Leu35Pro), TOPMed rs1391419251, gnomAD rs1391419251, REVEL 0.55, MetaLR 0.81
- L35V (p.Leu35Val), ExAC rs201899558, TOPMed rs201899558, gnomAD rs201899558
- E36A (p.Glu36Ala), Ensembl rs2128155713
- E36D (p.Glu36Asp), Ensembl rs2128155723
- E36G (p.Glu36Gly), Ensembl rs2128155713, REVEL 0.52, MetaLR 0.73
- E36K (p.Glu36Lys), Ensembl rs2128155704
- E36Q (p.Glu36Gln), Ensembl rs2128155704
- E36V (p.Glu36Val), Ensembl rs2128155713
- p.Glu36 Leu39del, gnomAD 6-151808011-CCCCC, CADD 22.40
- R37G (p.Arg37Gly), Ensembl rs2128155727
- R37L (p.Arg37Leu), cosmic curated COSV52800
- R37P (p.Arg37Pro), Ensembl rs2128155730
- R37Q (p.Arg37Gln), Ensembl rs2128155730
- R37W (p.Arg37Trp), Ensembl rs2128155727, REVEL 0.59, MetaLR 0.73
- P38A (p.Pro38Ala), Ensembl rs2128155734
- P38F (p.Pro38Phe), cosmic curated COSV10506
- P38L (p.Pro38Leu), Ensembl rs2128155744
- P38R (p.Pro38Arg), Ensembl rs2128155744
- P38S (p.Pro38Ser), Ensembl rs2128155734
- L39M (p.Leu39Met), ExAC rs781772511, gnomAD rs781772511, REVEL 0.48, MetaLR 0.83, Likely benign
- L39Q (p.Leu39Gln), Ensembl rs2128155780
- L39V (p.Leu39Val), ExAC rs781772511, gnomAD rs781772511, Likely benign
- G40A (p.Gly40Ala), Ensembl rs2128155805
- G40C (p.Gly40Cys), Ensembl rs2128155798
- G40D (p.Gly40Asp), Ensembl rs2128155805
- G40R (p.Gly40Arg), Ensembl rs2128155798
- G40V (p.Gly40Val), NCI-TCGA Cosmic COSV5279, cosmic curated COSV52798, Variant assessed as somatic; moderate impact.
- G40S (p.Gly40Ser), gnomAD 6-151808030-G-A, REVEL 0.18, MetaLR 0.23
- G40G (p.Gly40Gly), rs2128155816, gnomAD 6-151808032-C-T, CADD 15.20
- E41* (p.Glu41Ter), Ensembl rs2128155824
- E41D (p.Glu41Asp), NCI-TCGA Cosmic COSV9923, cosmic curated COSV99239, Ensembl rs2128155839, Variant assessed as somatic; moderate impact.
Public ESR1 analysis runs
- ESR1 analysis run — ESR1 (2,664 variants) — completed 2026-08-10