Is BRCA2 p.Ala186= (c.558T>C) pathogenic?

BRCA2 p.Ala186= (c.558T>C) is classified Likely benign in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-02). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ala186= (c.558T>C)?

BRCA2 p.Ala186= (c.558T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ala186= (c.558T>C) in the general population?

BRCA2 p.Ala186= (c.558T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

BRCA2 p.Ala186=

c.558T>C · rs1555281062 · VCV1748488

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.67	GERP -4.5, phastCons 0.034
Overall
CADD	8.072	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,950 alleles

Overall 0.000124% 2/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,950
European (non-Finnish)	8.48e-05%	1,179,930

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.Ala186=
Coding: c.558T>C
MANE Select: NM_000059
dbSNP: rs1555281062
Type: single nucleotide variant
Location: chr13:32326540 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

Full BRCA2 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

Similar variants

BRCA2 p.Ala186Pro Uncertain significance ★★ ⚠ same residue
BRCA2 p.Ala186Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala186_Asp189del Uncertain significance ★ same residue
BRCA2 p.Ala186Ser Uncertain significance ★ ⚠ same residue
BRCA2 p.Ala186Val Uncertain significance ★ ⚠ 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

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-ala186 (accessed [today's date]).

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