Is ESR1 p.Lys299Arg (c.896A>G) pathogenic?

ESR1 p.Lys299Arg (c.896A>G) is classified Uncertain significance in ESR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-02-23). AlphaMissense: likely benign (0.0758); Rare (popmax 0.185%, nfe).

How common is ESR1 p.Lys299Arg (c.896A>G) in the general population?

ESR1 p.Lys299Arg (c.896A>G) is rare (popmax 0.185%, nfe) (gnomAD).

What do computational predictors say about ESR1 p.Lys299Arg (c.896A>G)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

ESR1 p.Lys299Arg

c.896A>G · rs77797873 · VCV1193136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 64 kb · p 0.98 · regional, not allelic
Overall
CADD	19.47	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 0.185% European (non-Finnish) · 2,186/1,180,024 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.145% 2,339/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.185%	540
Remaining individualsnot grpmax-eligible	0.104%	962
South Asian	0.0428%	2,335
Admixed American	0.0383%	2,610
Middle Eastern	0.033%	3,031
African / African-American	0.0293%	3,411
Finnishnot grpmax-eligible	0.00312%	32,019

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.Lys299Arg
Coding: c.896A>G
MANE Select: NM_000125
dbSNP: rs77797873
Type: single nucleotide variant
Location: chr6:151944308 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 299: the 'hinge' region; the 'interaction with akap13' region; the 'self-association' region; the 'mediates interaction with dnttip2' 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
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
SYNE1 p.Gly8737Val 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-lys299arg (accessed [today's date]).

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