Is BRCA2 p.Ala1799Thr (c.5395G>A) pathogenic?

BRCA2 p.Ala1799Thr (c.5395G>A) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-03-23). AlphaMissense: likely benign (0.069); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Ala1799Thr (c.5395G>A)?

BRCA2 p.Ala1799Thr (c.5395G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Ala1799Thr (c.5395G>A) in the general population?

BRCA2 p.Ala1799Thr (c.5395G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Ala1799Thr (c.5395G>A)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

BRCA2 p.Ala1799Thr

c.5395G>A · rs2137517102 · VCV1423126

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.1	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -4.9
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	0.189	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,858 alleles

Overall 6.84e-05% 1/1,461,632 alleles · very rare

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.Ala1799Thr
Coding: c.5395G>A
MANE Select: NM_000059
dbSNP: rs2137517102
Type: single nucleotide variant
Location: chr13:32339750 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1799: the 'interaction with rad51' region

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

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Ala1799Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala1799Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ala1799= Likely benign ★ same residue
BRCA2 p.Ala1799_Tyr1800insSerLeuSerLeuSerLeuSerLeuSerLeuSerLeuSerProArgSerProSerThrValSerLeuTer 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-ala1799thr (accessed [today's date]).

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