Is BRCA1 p.Arg1751Leu (c.5252G>T) pathogenic?

BRCA1 p.Arg1751Leu (c.5252G>T) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.3294); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA1 p.Arg1751Leu (c.5252G>T)?

BRCA1 p.Arg1751Leu (c.5252G>T) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Arg1751Leu (c.5252G>T) in the general population?

BRCA1 p.Arg1751Leu (c.5252G>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA1 p.Arg1751Leu (c.5252G>T)?

AlphaMissense predicts likely benign (score 0.3294) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg1751Leu

c.5252G>T · rs80357442 · VCV531284

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3294 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.3294	likely benign
REVEL	0.727	pathogenic-leaning
SaProt	LLR -6.39	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.8	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.Arg1751Leu
Coding: c.5252G>T
MANE Select: NM_007294
dbSNP: rs80357442
Type: single nucleotide variant
Location: chr17:43057077 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1751: a UniProt-annotated variant site (in fancs); an α-helix

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

Disease context

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

Also linked: hereditary neoplastic syndrome

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Arg1751Pro Likely pathogenic ★★★ same residue
BRCA1 p.Arg1751Ter Pathogenic ★★★ same residue
BRCA1 p.Arg1751Gln Benign ★★★ ⚠ same residue
BRCA1 p.Arg1751= Likely benign ★★ same residue
BRCA1 p.Arg1751Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Arg1751fs Pathogenic ★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T 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-arg1751leu (accessed [today's date]).

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