Is BRCA1 p.Ser1448= (c.4344C>T) pathogenic?

BRCA1 p.Ser1448= (c.4344C>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-18). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ser1448= (c.4344C>T)?

BRCA1 p.Ser1448= (c.4344C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Ser1448= (c.4344C>T) in the general population?

BRCA1 p.Ser1448= (c.4344C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

BRCA1 p.Ser1448=

c.4344C>T · rs1250691798 · VCV479268

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.053	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.33, phastCons 0.014
Overall
CADD	6.772	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,900 alleles

Overall 6.2e-05% 1/1,613,700 alleles · very rare exomes 0/1,461,544 · genomes 1/152,156 · joint denominator

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.Ser1448=
Coding: c.4344C>T
MANE Select: NM_007294
dbSNP: rs1250691798
Type: single nucleotide variant
Location: chr17:43082417 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1448: the 'disordered' region; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally neutral in vitro)

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 breast-ovarian cancer, familial, susceptibility to, 1

Similar variants

BRCA1 p.Ser1448Arg Uncertain significance ★ ⚠ same residue
BRCA1 p.Ser1448Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1448Gly Conflicting classifications of pathogenicity ★ ⚠ 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
BRCA1 c.212+3A>G 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-ser1448 (accessed [today's date]).

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