Is BRCA1 p.Cys348Phe (c.1043G>T) pathogenic?

BRCA1 p.Cys348Phe (c.1043G>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1037); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Cys348Phe (c.1043G>T)?

BRCA1 p.Cys348Phe (c.1043G>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Cys348Phe (c.1043G>T) in the general population?

BRCA1 p.Cys348Phe (c.1043G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Cys348Phe (c.1043G>T)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

BRCA1 p.Cys348Phe

c.1043G>T · rs752198747 · VCV2092620

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.569	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -5.2
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	0.038	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.Cys348Phe
Coding: c.1043G>T
MANE Select: NM_007294
dbSNP: rs752198747
Type: single nucleotide variant
Location: chr17:43094488 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

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.Cys348Ter Pathogenic ★★★ same residue
BRCA1 p.Cys348Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Cys348Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Cys348_Glu349delinsTer Pathogenic ★★★ same residue
BRCA1 p.Cys348fs 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-cys348phe (accessed [today's date]).

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