Is BRCA1 p.Ala253Glu (c.758C>A) pathogenic?

BRCA1 p.Ala253Glu (c.758C>A) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.166); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ala253Glu (c.758C>A)?

BRCA1 p.Ala253Glu (c.758C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Ala253Glu (c.758C>A) in the general population?

BRCA1 p.Ala253Glu (c.758C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRCA1 p.Ala253Glu (c.758C>A)?

AlphaMissense predicts likely benign (score 0.166) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala253Glu

c.758C>A · rs1555593177 · VCV1759651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.166	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -5.49	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 4.1	GERP -1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	20.9	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 0.0011% South Asian · 1/90,820 alleles

Overall 6.85e-05% 1/1,459,792 alleles · very rare

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: BRCA1
Protein: p.Ala253Glu
Coding: c.758C>A
MANE Select: NM_007294
dbSNP: rs1555593177
Type: single nucleotide variant
Location: chr17:43094773 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 253: the 'disordered' region

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.Ala253Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ala253Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ala253= Likely benign ★ 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-ala253glu (accessed [today's date]).

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