Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
low-frequency (popmax 2.06%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.5 | GERP -3.2 |
| Overall | ||
| CADD | 0.464 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
2.06%
African / African-American · 1,544/75,038 alleles
Filtering AF
1.97%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.94%
Overall
0.11%
1,781/1,614,184 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 2.06% | 49 |
| Remaining individualsnot grpmax-eligible | 0.165% | 607 |
| Admixed American | 0.157% | 639 |
| Middle Eastern | 0.115% | 866 |
| South Asian | 0.00329% | 30,363 |
| European (non-Finnish) | 0.00254% | 39,334 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- ESR1
- Protein
- p.Ala558=
- Coding
- c.1674A>G
- MANE Select
- NM_000125
- dbSNP
- rs9341068
- Type
- single nucleotide variant
- Location
- chr6:152098852 (GRCh38)
- Gene constraint
- LOEUF 0.456 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 67.14 · 492 PDB
- Residue 558
- the 'interaction with akap13' region; the 'self-association' region; the 'transactivation af-2' region; the 'disordered' region
Similar variants
- SYNE1 p.Arg8746Ter Pathogenic/Likely pathogenic ★★ same type
- ESR1 p.Lys299Arg Uncertain significance ★★ ⚠ same type
- SYNE1 p.Arg8735Leu Uncertain significance ★★ ⚠ same type
- SYNE1 p.Arg8738His Uncertain significance ★★ ⚠ same type
- SYNE1 p.Arg8746Gln Uncertain significance ★★ same type
- SYNE1 p.Arg8782Gln Uncertain significance ★★ same type
- SYNE1 p.Arg8782Gly Uncertain significance ★★ same type
- SYNE1 p.Asp8725Asn Uncertain significance ★★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/esr1-p-ala558 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown