Is ESR2 p.Ser264Arg (c.792C>A) pathogenic?

ESR2 p.Ser264Arg (c.792C>A) is classified Uncertain significance in ESR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). AlphaMissense: ambiguous (0.5324); Very rare (popmax 0.00267%, afr).

How common is ESR2 p.Ser264Arg (c.792C>A) in the general population?

ESR2 p.Ser264Arg (c.792C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ESR2 p.Ser264Arg (c.792C>A)?

AlphaMissense predicts ambiguous (score 0.5324) — an in-silico prediction, not a clinical call.

ESR2 p.Ser264Arg

c.792C>A · rs760331553 · VCV3090544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5324	ambiguous
REVEL	0.67	pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.36, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 50 kb · p 0.43 · regional, not allelic
Overall
CADD	21.2	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 0.00267% African / African-American · 2/74,842 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,610,704 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,421
European (non-Finnish)	0.00017%	589,140

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: ESR2
Protein: p.Ser264Arg
Coding: c.792C>A
MANE Select: NM_001437
dbSNP: rs760331553
Type: single nucleotide variant
Location: chr14:64260609 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.76 · 39 PDB
Residue 264: the nr lbd domain

Full ESR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESR2 p.Ala432Thr Uncertain significance ★★ ⚠ same type
ESR2 p.Arg230Gln Uncertain significance ★★ ⚠ same type
ESR2 p.Arg346Cys Uncertain significance ★★ ⚠ same type
ESR2 p.Arg388Gln Uncertain significance ★★ ⚠ same type
ESR2 p.Asn407Ser Uncertain significance ★★ ⚠ same type
ESR2 p.Asp154Asn Uncertain significance ★★ ⚠ same type
ESR2 p.Cys169Phe Uncertain significance ★★ ⚠ same type
ESR2 p.Gly243Asp 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/esr2-p-ser264arg (accessed [today's date]).

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