Is ESR1 p.Phe97Ser (c.290T>C) pathogenic?

ESR1 p.Phe97Ser (c.290T>C) is classified Uncertain significance in ESR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: ambiguous (0.3507); Very rare (popmax 0.00121%, nfe).

How common is ESR1 p.Phe97Ser (c.290T>C) in the general population?

ESR1 p.Phe97Ser (c.290T>C) is very rare (popmax 0.00121%, nfe) (gnomAD).

What do computational predictors say about ESR1 p.Phe97Ser (c.290T>C)?

AlphaMissense predicts ambiguous (score 0.3507) — an in-silico prediction, not a clinical call.

ESR1 p.Phe97Ser

c.290T>C · rs1356923842 · VCV2605126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00121%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3507	ambiguous
REVEL	0.101	moderately benign-leaning
SaProt	LLR -5.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.17, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 35 kb · p 0.76 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00121% European (non-Finnish) · 14/1,158,762 alleles

Filtering AF 0.000701% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000548%

Overall 0.000891% 14/1,571,382 alleles · very rare

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.Phe97Ser
Coding: c.290T>C
MANE Select: NM_000125
dbSNP: rs1356923842
Type: single nucleotide variant
Location: chr6:151808202 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 97: the 'modulating (transactivation af-1); mediates interaction with macrod1' region; the 'interaction with ddx5; self-association' region

Full ESR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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-phe97ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown