Is BRCA1 p.Arg1699Trp (c.5095C>T) pathogenic?

BRCA1 p.Arg1699Trp (c.5095C>T) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 47 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.8237); Ultra-rare (popmax 0.0164%, mid); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Arg1699Trp (c.5095C>T)?

BRCA1 p.Arg1699Trp (c.5095C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1, endometrial carcinoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Arg1699Trp (c.5095C>T) in the general population?

BRCA1 p.Arg1699Trp (c.5095C>T) is ultra-rare (popmax 0.0164%, mid) (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.Arg1699Trp (c.5095C>T)?

AlphaMissense predicts likely pathogenic (score 0.8237) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg1699Trp

c.5095C>T · rs55770810 · VCV55396

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 47 submitters

AlphaMissense

likely pathogenic

0.8237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.8237	likely pathogenic ✓ concordant with ClinVar · top 4% in BRCA1
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	33.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000806% 13/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.00469%	21,338
East Asian	0.00223%	44,864
South Asian	0.0011%	91,076
European (non-Finnish)	0.000593%	168,562

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.Arg1699Trp
Coding: c.5095C>T
MANE Select: NM_007294
dbSNP: rs55770810
Type: single nucleotide variant
Location: chr17:43063931 (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

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma hereditary breast ovarian cancer syndrome breast cancer ovarian cancer Fanconi anemia complementation group A hereditary neoplastic syndrome hereditary breast carcinoma Fanconi anemia, complementation group S BRCA1-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Arg1699Gln Pathogenic ★★★ same residue
BRCA1 p.Arg1699Pro Uncertain significance ★★★ ⚠ 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-arg1699trp (accessed [today's date]).

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