Is BRCA1 p.Gly1748Arg (c.5242G>C) pathogenic?

BRCA1 p.Gly1748Arg (c.5242G>C) is classified Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-30). AlphaMissense: likely pathogenic (0.9862); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Gly1748Arg (c.5242G>C)?

BRCA1 p.Gly1748Arg (c.5242G>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Gly1748Arg (c.5242G>C) in the general population?

BRCA1 p.Gly1748Arg (c.5242G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Gly1748Arg (c.5242G>C)?

AlphaMissense predicts likely pathogenic (score 0.9862) — an in-silico prediction, not a clinical call.

BRCA1 p.Gly1748Arg

c.5242G>C · rs397507245 · VCV240819

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9862 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9862	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.703	pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.6	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.Gly1748Arg
Coding: c.5242G>C
MANE Select: NM_007294
dbSNP: rs397507245
Type: single nucleotide variant
Location: chr17:43057087 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1748: 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 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.Gly1748Cys Likely pathogenic ★★★ same residue
BRCA1 p.Gly1748Asp Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Gly1748Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Gly1748Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Gly1748fs 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-gly1748arg (accessed [today's date]).

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