Is BRCA1 p.Arg1762Met (c.5285G>T) pathogenic?

BRCA1 p.Arg1762Met (c.5285G>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.1332); Very rare (popmax 0.000339%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Arg1762Met (c.5285G>T)?

BRCA1 p.Arg1762Met (c.5285G>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Arg1762Met (c.5285G>T) in the general population?

BRCA1 p.Arg1762Met (c.5285G>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Arg1762Met (c.5285G>T)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg1762Met

c.5285G>T · rs398122694 · VCV91646

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -8.12	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 -2.8	GERP -5.4
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	16.43	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 0.000339% European (non-Finnish) · 4/1,179,878 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,710 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.Arg1762Met
Coding: c.5285G>T
MANE Select: NM_007294
dbSNP: rs398122694
Type: single nucleotide variant
Location: chr17:43051110 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1762: a UniProt-annotated variant site (in fancs); the brct 2 domain; a turn

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

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1

Similar variants

BRCA1 p.Arg1762= Likely benign ★★ same residue
BRCA1 p.Arg1762Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Arg1762Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Arg1762Trp Uncertain significance ★ ⚠ same residue
BRCA1 p.Arg1762fs Pathogenic ★★★ 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

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-arg1762met (accessed [today's date]).

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