ESR1

Chr 6

estrogen receptor 1

Also known as: ER, ESR, ESRA, ESTRR, Era, NR3A1

NCBI Gene: 2099 ENSG00000091831 UniProt: P03372

The estrogen receptor 1 protein functions as a ligand-activated transcription factor that regulates estrogen-responsive genes involved in growth, metabolism, and sexual development. Mutations cause estrogen resistance syndrome with autosomal recessive inheritance, while some variants may contribute to migraine susceptibility with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variation (pLI 0.99, LOEUF 0.19), indicating that complete loss of function is likely incompatible with normal development.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEstrogen resistance

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

1443

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.45

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.61Z-score

OE missense 0.75 (0.68–0.84)

258 obs / 341.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.75 (0.68–0.84)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 1 / 25.0Missense obs/exp: 258 / 341.9Syn Z: -1.24

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ESR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Anatomic Stage II Breast Cancer AJCC v8Anatomic Stage IIA Breast Cancer AJCC v8Anatomic Stage IIB Breast Cancer AJCC v8

CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients After Pre-surgery Chemo and Targeted Therapy

ACTIVE NOT RECRUITING

NCT04266249Phase PHASE2ECOG-ACRIN Cancer Research GroupStarted 2020-03-13

DocetaxelLumpectomyMastectomy

Breast Cancer

Preoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer

ACTIVE NOT RECRUITING

NCT02955394Phase PHASE2University of Colorado, DenverStarted 2017-09-21

EnzalutamideFulvestrant

Primary Invasive Breast CancerEstrogen Receptor Positive TumorHuman Epidermal Growth Factor Receptor 2 Negative Tumor

Reaching for Evidence-baSed Chemotherapy Use in Endocrine Sensitive Breast Cancer

ACTIVE NOT RECRUITING

NCT03503799North Eastern German Society of Gynaecological OncologyStarted 2018-07-17

Observation

Breast Cancer, Metastatic

Integrated Testing Strategy for Simultaneous Detection of ESR-1 and gBRCA Mutations Via Liquid Biopsy in HR+/HER2- Metastatic Breast Cancer (mBC) Patients,

RECRUITING

NCT06762483European Institute of OncologyStarted 2024-12-20

Breast CancerDuctal CarcinomaEstrogen-receptor-positive Breast Cancer

Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer

NOT YET RECRUITING

NCT07499999Phase PHASE2Dana-Farber Cancer InstituteStarted 2026-09-09

ExemestaneTamoxifen

Central Nervous System (CNS) MetastasesBreast Cancer

A Phase II Observational Clinical Study on the Relationship Between Cerebrospinal Fluid Drug Concentration and Efficacy of Trastuzumab Deruxtecan in Central Nervous System Metastatic Breast Cancer

RECRUITING

NCT07653893Fudan UniversityStarted 2025-06-11

No Interventions

HER 2 Negative Breast Cancer

A Multicenter, Single-Arm, Phase II Exploratory Study of Eribulin in Combination With Anlotinib for HER2-Negative Recurrent/Metastatic Breast Cancer Previously Treated With Antibody-Drug Conjugates

RECRUITING

NCT07520760Phase PHASE2Sun Yat-sen UniversityStarted 2026-04-01

Eribulin in Combination with Anlotinib

Ductal Breast Carcinoma in Situ

Surgical Excision vs Neoadjuvant Radiotherapy+Delayed Surgical Excision of Ductal Carcinoma

RECRUITING

NCT03909282Phase NAStanford UniversityStarted 2019-03-22

LumpectomyPartial breast irradiation prior to surgery

Primary Breast CancerRecurrent/Metastatic Breast Cancer

Breast Cancer Proteomics and Molecular Heterogeneity

RECRUITING

NCT01840293Cancer Trials IrelandStarted 2013-02