Is BRCA1 p.Gln126= (c.378A>G) pathogenic?

BRCA1 p.Gln126= (c.378A>G) is classified Likely benign in BRCA1 (ClinVar, Expert panel, 8 submitters; last evaluated 2017-06-29). Very rare (popmax 0.00237%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Gln126= (c.378A>G)?

BRCA1 p.Gln126= (c.378A>G) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Gln126= (c.378A>G) in the general population?

BRCA1 p.Gln126= (c.378A>G) is very rare (popmax 0.00237%, nfe) (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.

BRCA1 p.Gln126=

c.378A>G · rs786201256 · VCV184064

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.211	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.52	GERP -0.54, phastCons 0.11
Overall
CADD	6.615	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,179,958 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00173% 28/1,613,972 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.Gln126=
Coding: c.378A>G
MANE Select: NM_007294
dbSNP: rs786201256
Type: single nucleotide variant
Location: chr17:43104185 (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

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

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Gln126Ter Pathogenic ★★★ same residue
BRCA1 p.Gln126Arg Uncertain significance ★★ ⚠ same residue
BRCA1 p.Gln126His Uncertain significance ★ ⚠ same residue
BRCA1 p.Gln126fs 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
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-gln126 (accessed [today's date]).

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