Is BRCA2 p.Arg3302Ser (c.9906G>T) pathogenic?

BRCA2 p.Arg3302Ser (c.9906G>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-08). AlphaMissense: likely pathogenic (0.8574); Very rare (popmax 8.47e-05%, nfe); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Arg3302Ser (c.9906G>T)?

BRCA2 p.Arg3302Ser (c.9906G>T) is associated with BRCA2-related cancer predisposition, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Arg3302Ser (c.9906G>T) in the general population?

BRCA2 p.Arg3302Ser (c.9906G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Arg3302Ser (c.9906G>T)?

AlphaMissense predicts likely pathogenic (score 0.8574) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg3302Ser

c.9906G>T · rs786203842 · VCV187584

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.8574	likely pathogenic · top 2% in BRCA2
REVEL	0.158	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.34, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	22.3	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.84e-05% 1/1,461,874 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.Arg3302Ser
Coding: c.9906G>T
MANE Select: NM_000059
dbSNP: rs786203842
Type: single nucleotide variant
Location: chr13:32398419 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3302: the 'tr2 region' region

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

Disease context

Also linked: hereditary neoplastic syndrome

Similar variants

BRCA2 p.Arg3302= Likely benign ★★★ same residue
BRCA2 p.Arg3302Gly Uncertain significance ★★ ⚠ same residue
BRCA2 p.Arg3302Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg3302_Ser3303delinsSerCys Uncertain significance ★★ same residue
BRCA2 p.Arg3302Thr 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-arg3302ser (accessed [today's date]).

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