Is BRCA1 p.Glu85Gln (c.253G>C) pathogenic?

BRCA1 p.Glu85Gln (c.253G>C) is classified Uncertain significance in BRCA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.3938); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Glu85Gln (c.253G>C)?

BRCA1 p.Glu85Gln (c.253G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Glu85Gln (c.253G>C) in the general population?

BRCA1 p.Glu85Gln (c.253G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Glu85Gln (c.253G>C)?

AlphaMissense predicts ambiguous (score 0.3938) — an in-silico prediction, not a clinical call.

BRCA1 p.Glu85Gln

c.253G>C · rs2054685109 · VCV868804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3938	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -5.83	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.32	donor loss, 48 bp away · raw score · deltas
Pangolin	Δ0.21	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA1
Protein: p.Glu85Gln
Coding: c.253G>C
MANE Select: NM_007294
dbSNP: rs2054685109
Type: single nucleotide variant
Location: chr17:43104916 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 85: an α-helix

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRCA1 p.Glu85= Likely benign ★★★ same residue
BRCA1 p.Glu85Lys Uncertain significance ★★ ⚠ same residue
BRCA1 p.Glu85Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G Pathogenic ★★★ same condition

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/brca1-p-glu85gln (accessed [today's date]).

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