Is BRCA1 p.Arg1699Pro (c.5096G>C) pathogenic?

BRCA1 p.Arg1699Pro (c.5096G>C) is classified Uncertain significance in BRCA1 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.9776); Absent from gnomAD v4.1; Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Arg1699Pro (c.5096G>C)?

BRCA1 p.Arg1699Pro (c.5096G>C) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Arg1699Pro (c.5096G>C) in the general population?

BRCA1 p.Arg1699Pro (c.5096G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Arg1699Pro (c.5096G>C)?

AlphaMissense predicts likely pathogenic (score 0.9776) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg1699Pro

c.5096G>C · rs41293459 · VCV55397

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9776 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.9776	likely pathogenic · top 1% in BRCA1
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	28.9	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

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

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PP3

Curation rationale (ClinGen, verbatim)

The c.5096G>C variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Proline at amino acid 1699 (p.(Arg1699Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies with discordant results. Functional effect similar to benign control variants (PMID:38709234) and to pathogenic control variants (PMID:30209399, 35196514) (PS3 and BS3 not met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.43, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold <0.10) (PP3 met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA1
Protein: p.Arg1699Pro
Coding: c.5096G>C
MANE Select: NM_007294
dbSNP: rs41293459
Type: single nucleotide variant
Location: chr17:43063930 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1699: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; pathogenic; strongly reduces affinity for a brip1 phosphopeptide; functionally impaired in vitro); a UniProt-annotated variant site (in bc, oc and fancs; impairs protein stability; functionally impaired in vitro)

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

Disease context

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

Similar variants

BRCA1 p.Arg1699Gln Pathogenic ★★★ same residue
BRCA1 p.Arg1699Trp Pathogenic ★★★ same residue
BRCA1 p.Arg1699Leu Likely pathogenic ★★ same residue
BRCA1 p.Arg1699= 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

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-arg1699pro (accessed [today's date]).

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