Is BRCA2 p.Thr582Pro (c.1744A>C) pathogenic?

BRCA2 p.Thr582Pro (c.1744A>C) is classified Benign in BRCA2 (ClinVar, Expert panel, 20 submitters; last evaluated 2015-08-10). AlphaMissense: likely benign (0.2942); Rare (popmax 0.35%, eas); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Thr582Pro (c.1744A>C)?

BRCA2 p.Thr582Pro (c.1744A>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Thr582Pro (c.1744A>C) in the general population?

BRCA2 p.Thr582Pro (c.1744A>C) is rare (popmax 0.35%, 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.

What do computational predictors say about BRCA2 p.Thr582Pro (c.1744A>C)?

AlphaMissense predicts likely benign (score 0.2942) — an in-silico prediction, not a clinical call.

BRCA2 p.Thr582Pro

c.1744A>C · rs80358457 · VCV37753

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.2942 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.35%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.2942	likely benign
REVEL	0.252	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.35% East Asian · 157/44,866 alleles

Filtering AF 0.305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.288%

Overall 0.00986% 159/1,613,026 alleles · rare exomes 150/1,460,680 · genomes 9/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.35%	286
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	8.48e-05%	1,179,376

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: BRCA2
Protein: p.Thr582Pro
Coding: c.1744A>C
MANE Select: NM_000059
dbSNP: rs80358457
Type: single nucleotide variant
Location: chr13:32333222 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 582: a UniProt-annotated variant site (in)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast cancer hereditary neoplastic syndrome hereditary breast carcinoma

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Thr582Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Thr582Ile Uncertain significance ★ ⚠ same residue
BRCA2 p.Thr582Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Thr582_Leu583insTer Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition
BRCA2 c.316+5G>C 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/brca2-p-thr582pro (accessed [today's date]).

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