Is BRCA1 p.Thr1449= (c.4347A>G) pathogenic?

BRCA1 p.Thr1449= (c.4347A>G) is classified Likely benign in BRCA1 (ClinVar, Expert panel, 15 submitters; last evaluated 2017-06-29). Rare (popmax 0.372%, eas); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Thr1449= (c.4347A>G)?

BRCA1 p.Thr1449= (c.4347A>G) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 p.Thr1449= (c.4347A>G) in the general population?

BRCA1 p.Thr1449= (c.4347A>G) is rare (popmax 0.372%, eas) (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.Thr1449=

c.4347A>G · rs80356840 · VCV55176

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

rare (popmax 0.372%, eas)

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	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -3.3
Overall
CADD	3.733	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.372% East Asian · 167/44,866 alleles

Filtering AF 0.326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.308%

Overall 0.0107% 172/1,614,020 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.372%	269
South Asian	0.00329%	30,357
Remaining individualsnot grpmax-eligible	0.0032%	31,251

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.Thr1449=
Coding: c.4347A>G
MANE Select: NM_007294
dbSNP: rs80356840
Type: single nucleotide variant
Location: chr17:43082414 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1449: the 'disordered' region; a UniProt-annotated variant site (in fancs)

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 breast cancer hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Thr1449Ile Uncertain significance ★★ ⚠ same residue
BRCA1 p.Thr1449Ala Uncertain significance ★ ⚠ same residue
BRCA1 p.Thr1449Pro Uncertain significance ★ ⚠ same residue
BRCA1 p.Thr1449fs 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-thr1449 (accessed [today's date]).

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