# NM_000125.4(ESR1):c.729= (p.Arg243=)

https://sugi.bio/variant/esr1-p-arg243

## Summary

**ESR1 p.Arg243= (c.729=)** is classified **Benign** in ESR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Absent from gnomAD v4.1.

**At a glance:** Benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ESR1 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ESR1](https://sugi.bio/atlas/gene/ESR1/) |
| Protein change (HGVS p.) | p.Arg243= |
| Coding change (HGVS c.) | c.729= |
| MANE Select transcript | [NM_000125](https://www.ncbi.nlm.nih.gov/nuccore/NM_000125) |
| Variant type | Variation |
| Location | chr6:151880740-151880740 (GRCh38) |
| ClinVar | [VCV770366](https://www.ncbi.nlm.nih.gov/clinvar/variation/770366/) |

**All HGVS expressions:** `LRG_992:g.229050C>T`, `LRG_992t1:c.729C>T`, `NC_000006.11:g.152201875=`, `NC_000006.12:g.151880740=`, `NG_008493.2:g.229050C>T`, `NM_000125.4:c.729=`, `NM_001122740.2:c.729=`, `NM_001122741.2:c.729=`, `NM_001122742.2:c.729=`, `NM_001291230.2:c.735=`, `NM_001291241.2:c.729=`, `NM_001328100.2:c.210=`, `NM_001385568.1:c.729=`, `NM_001385569.1:c.729=`, `NM_001385570.1:c.729=`, `NM_001385571.1:c.729=`, `NM_001385572.1:c.729=`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.133, GERP -5.07, phastCons 0.921 — weakly conserved position
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ESR1** population constraint: LOEUF 0.456, pLI 0.99795, missense-Z 2.4607. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **243** lies in a DNA-binding region; an α-helix; the 'mediates interaction with dnttip2' region.

AlphaFold model confidence (whole protein): pLDDT 67.14, 45% of residues very-high.

**492 experimental structure(s)** (PDB): [11SD](https://www.rcsb.org/structure/11SD), [11SE](https://www.rcsb.org/structure/11SE), [11SF](https://www.rcsb.org/structure/11SF), [11SG](https://www.rcsb.org/structure/11SG), [11SH](https://www.rcsb.org/structure/11SH), [11SI](https://www.rcsb.org/structure/11SI) — incl. mutant structure 1QKT.

## What this gene does {#gene-function}

*Describes the biological roles of ESR1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ESR1's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Arg243= falls in a DNA-binding region. In Reactome, ESR1 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** ESR1 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

ESR1 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [Developmental Lineage of Mammary Gland Alveolar Cells](https://reactome.org/content/detail/R-HSA-9927426) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [ESR-mediated signaling](https://reactome.org/content/detail/R-HSA-8939211) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [Mitochondrial unfolded protein response (UPRmt)](https://reactome.org/content/detail/R-HSA-9841251) | curated |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RUNX1 regulates estrogen receptor mediated transcription](https://reactome.org/content/detail/R-HSA-8931987) | curated |
| [RUNX1 regulates transcription of genes involved in WNT signaling](https://reactome.org/content/detail/R-HSA-8939256) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |
| [TFAP2 (AP-2) family regulates transcription of growth factors and their receptors](https://reactome.org/content/detail/R-HSA-8866910) | curated |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, TFIIB-class transcription factor binding, transcription coregulator binding, transcription corepressor binding, transcription coactivator binding, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of gene expression, estrogen receptor signaling pathway, response to estradiol, negative regulation of canonical NF-kappaB signal transduction, steroid hormone receptor signaling pathway.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ESR1 variant pages (same residue, condition, or type): [ESR1 p.Pro325=](/variant/esr1-p-pro325).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 770366). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*