Is BRCA1 p.Cys1372Arg (c.4114T>C) pathogenic?

BRCA1 p.Cys1372Arg (c.4114T>C) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-23). AlphaMissense: likely benign (0.1464); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Cys1372Arg (c.4114T>C)?

BRCA1 p.Cys1372Arg (c.4114T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Cys1372Arg (c.4114T>C) in the general population?

BRCA1 p.Cys1372Arg (c.4114T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Cys1372Arg (c.4114T>C)?

AlphaMissense predicts likely benign (score 0.1464) — an in-silico prediction, not a clinical call.

BRCA1 p.Cys1372Arg

c.4114T>C · VCV3572269

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1464	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -5.69	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 3.5	GERP -1.1, phastCons 0.92
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	17.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,530 alleles

Overall 6.85e-05% 1/1,460,458 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.Cys1372Arg
Coding: c.4114T>C
MANE Select: NM_007294
Type: single nucleotide variant
Location: chr17:43091015 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1372: a UniProt-annotated variant site (in fancs); the 'disordered' region

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

Similar variants

BRCA1 p.Cys1372Phe Uncertain significance ★★ ⚠ same residue
BRCA1 p.Cys1372Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Cys1372_Glu1373delinsTer Pathogenic ★★★ same residue
BRCA1 p.Cys1372fs Pathogenic ★★★ same residue
BRCA1 p.Cys1372Ter 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-cys1372arg (accessed [today's date]).

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