Is ESR1 p.Pro295= (c.885G>A) pathogenic?

ESR1 p.Pro295= (c.885G>A) is classified Likely benign in ESR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-23). Ultra-rare (popmax 0.0467%, afr).

How common is ESR1 p.Pro295= (c.885G>A) in the general population?

ESR1 p.Pro295= (c.885G>A) is ultra-rare (popmax 0.0467%, afr) (gnomAD).

ESR1 p.Pro295=

c.885G>A · rs368367164 · VCV754648

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.037	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -4
Overall
CADD	0.339	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% African / African-American · 35/75,018 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.0286% 461/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.089%	1,123
African / African-Americangrpmax	0.0467%	2,143
European (non-Finnish)	0.0297%	3,371
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.01%	10,004
South Asian	0.00329%	30,359

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro295=
Coding: c.885G>A
MANE Select: NM_000125
dbSNP: rs368367164
Type: single nucleotide variant
Location: chr6:151944297 (GRCh38)
Gene constraint: LOEUF 0.456 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.14 · 492 PDB
Residue 295: 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
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-pro295 (accessed [today's date]).

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