# NM_001437.3(ESR2):c.693A>G (p.Arg231=)

https://sugi.bio/variant/esr2-p-arg231

## Summary

**ESR2 p.Arg231= (c.693A>G)** is classified **Likely benign** in ESR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-30). Very rare (popmax 0.00242%, sas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs767711085 · 3 submitters · very rare (popmax 0.00242%, sas)

## For patients & families {#patients}

This is a change in the ESR2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [ESR2](https://sugi.bio/atlas/gene/ESR2/) |
| Protein change (HGVS p.) | p.Arg231= |
| Coding change (HGVS c.) | c.693A>G |
| MANE Select transcript | [NM_001437](https://www.ncbi.nlm.nih.gov/nuccore/NM_001437) |
| dbSNP | [rs767711085](https://www.ncbi.nlm.nih.gov/snp/rs767711085/) |
| Variant type | single nucleotide variant |
| Location | chr14:64260708-64260708 (GRCh38) |
| ClinVar | [VCV1335149](https://www.ncbi.nlm.nih.gov/clinvar/variation/1335149/) |

**All HGVS expressions:** `NC_000014.8:g.64727426T>C`, `NC_000014.9:g.64260708T>C`, `NG_011535.1:g.82843A>G`, `NM_001040275.1:c.693A>G`, `NM_001214902.1:c.693A>G`, `NM_001271876.1:c.693A>G`, `NM_001271877.1:c.693A>G`, `NM_001291712.2:c.693A>G`, `NM_001291723.1:c.693A>G`, `NM_001437.2:c.693A>G`, `NM_001437.3:c.693A>G`, `NR_073496.2:n.1499A>G`, `NR_073497.1:n.610A>G`

## 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 -0.107, GERP -2, phastCons 0.663 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.513**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- 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 (gnomAD v4.1): grpmax **0.00242%** (sas) · FAF95 0.00106% · FAF99 0.000855% · 2/82,780 in the highest group · 23/1,551,486 alleles overall — very rare (popmax 0.00242%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00335% | 29,857 |
| South Asian (grpmax) | 0.00242% | 41,390 |
| European (non-Finnish) | 0.00166% | 60,289 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ESR2** population constraint: LOEUF 1.002, pLI 5.9579e-10, missense-Z -0.14268. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.76, 46% of residues very-high.

**39 experimental structure(s)** (PDB): [1L2J](https://www.rcsb.org/structure/1L2J), [1NDE](https://www.rcsb.org/structure/1NDE), [1QKM](https://www.rcsb.org/structure/1QKM), [1U3Q](https://www.rcsb.org/structure/1U3Q), [1U3R](https://www.rcsb.org/structure/1U3R), [1U3S](https://www.rcsb.org/structure/1U3S).

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

*Describes the biological roles of ESR2 (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:** ESR2's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. In Reactome, ESR2 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** ESR2 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

ESR2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [ESR-mediated signaling](https://reactome.org/content/detail/R-HSA-8939211) | curated |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | 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 |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, nuclear receptor activity, enzyme binding, nuclear estrogen receptor activity, estrogen response element binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, estrogen receptor signaling pathway, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II, cellular response to estradiol stimulus.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-30.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-08-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-30 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-01 |

**Reported phenotype names (ClinVar):** not provided, ESR2-related disorder, ESR2-related condition, none provided.

## Similar variants {#similar}

Related ESR2 variant pages (same residue, condition, or type): [ESR2 p.Ala432Thr](/variant/esr2-p-ala432thr), [ESR2 p.Arg230Gln](/variant/esr2-p-arg230gln), [ESR2 p.Arg346Cys](/variant/esr2-p-arg346cys), [ESR2 p.Arg388Gln](/variant/esr2-p-arg388gln), [ESR2 p.Asn407Ser](/variant/esr2-p-asn407ser), [ESR2 p.Asp154Asn](/variant/esr2-p-asp154asn), [ESR2 p.Cys169Phe](/variant/esr2-p-cys169phe), [ESR2 p.Gly243Asp](/variant/esr2-p-gly243asp).

### 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 1335149). 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.*