Is BRCA1 p.Gln1409His (c.4227G>C) pathogenic?

BRCA1 p.Gln1409His (c.4227G>C) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-09). AlphaMissense: likely benign (0.2522); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Gln1409His (c.4227G>C)?

BRCA1 p.Gln1409His (c.4227G>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Gln1409His (c.4227G>C) in the general population?

BRCA1 p.Gln1409His (c.4227G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA1 p.Gln1409His (c.4227G>C)?

AlphaMissense predicts likely benign (score 0.2522) — an in-silico prediction, not a clinical call.

BRCA1 p.Gln1409His

c.4227G>C · rs786201618 · VCV2774838

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2522	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.79, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.6	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 0.00223% East Asian · 1/44,888 alleles

Overall 6.84e-05% 1/1,461,882 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.Gln1409His
Coding: c.4227G>C
MANE Select: NM_007294
dbSNP: rs786201618
Type: single nucleotide variant
Location: chr17:43082534 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1409: the 'interaction with palb2' region; a UniProt-annotated variant site (in fancs)

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.Gln1409Ter Pathogenic ★★★ same residue
BRCA1 p.Gln1409= Likely benign ★★★ same residue
BRCA1 p.Gln1409Leu Uncertain significance ★★ ⚠ same residue
BRCA1 p.Gln1409_Glu1410insArg Uncertain significance ★ same residue
BRCA1 p.Gln1409Pro Uncertain significance ★ ⚠ 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-gln1409his (accessed [today's date]).

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