Is BRCA1 p.Ala1752Thr (c.5254G>A) pathogenic?

BRCA1 p.Ala1752Thr (c.5254G>A) is classified Uncertain significance in BRCA1 (ClinVar, Expert panel, 7 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.6574); Absent from gnomAD v4.1; Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Ala1752Thr (c.5254G>A)?

BRCA1 p.Ala1752Thr (c.5254G>A) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Ala1752Thr (c.5254G>A) in the general population?

BRCA1 p.Ala1752Thr (c.5254G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Ala1752Thr (c.5254G>A)?

AlphaMissense predicts likely pathogenic (score 0.6574) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala1752Thr

c.5254G>A · rs80357074 · VCV96944

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6574 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.6574	likely pathogenic · top 7% in BRCA1
REVEL	0.688	pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PS3 BP4

Curation rationale (ClinGen, verbatim)

The c.5254G>A variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1752 (p.(Ala1752Thr)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 30257991, 38709234) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.1, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (BP4 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.12 (based on Cosegregation LR=1.12), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, BP4).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA1
Protein: p.Ala1752Thr
Coding: c.5254G>A
MANE Select: NM_007294
dbSNP: rs80357074
Type: single nucleotide variant
Location: chr17:43057075 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1752: a UniProt-annotated variant site (in fancs); an α-helix

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome

Similar variants

BRCA1 p.Ala1752= Likely benign ★★★ same residue
BRCA1 p.Ala1752Pro Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Ala1752Gly Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1752Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1752Glu 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-ala1752thr (accessed [today's date]).

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