Is ESR1 p.Pro99Arg (c.296C>G) pathogenic?

ESR1 p.Pro99Arg (c.296C>G) is classified Uncertain significance in ESR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.1133); Very rare (popmax 0.00234%, eas).

How common is ESR1 p.Pro99Arg (c.296C>G) in the general population?

ESR1 p.Pro99Arg (c.296C>G) is very rare (popmax 0.00234%, eas) (gnomAD).

What do computational predictors say about ESR1 p.Pro99Arg (c.296C>G)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

ESR1 p.Pro99Arg

c.296C>G · rs773500294 · VCV3090530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.085	GERP -2.9, phastCons 0.002
Regional constraint	o/e 1.02	unconstrained · MANE · 35 kb · p 0.76 · regional, not allelic
Overall
CADD	16.05	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00234% East Asian · 1/42,784 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000211% 3/1,420,626 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00234%	42,784
European (non-Finnish)	0.000173%	579,619

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.Pro99Arg
Coding: c.296C>G
MANE Select: NM_000125
dbSNP: rs773500294
Type: single nucleotide variant
Location: chr6:151808208 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 99: 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

ESR1 p.Pro99Gln Uncertain significance ★ ⚠ same residue
ESR1 p.Pro99Leu Uncertain significance ★ ⚠ same residue
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

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-pro99arg (accessed [today's date]).

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