Is BRCA2 p.Asn3329Ser (c.9986A>G) pathogenic?

BRCA2 p.Asn3329Ser (c.9986A>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0582); Very rare (popmax 0.00534%, afr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Asn3329Ser (c.9986A>G)?

BRCA2 p.Asn3329Ser (c.9986A>G) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Asn3329Ser (c.9986A>G) in the general population?

BRCA2 p.Asn3329Ser (c.9986A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Asn3329Ser (c.9986A>G)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

BRCA2 p.Asn3329Ser

c.9986A>G · rs76635144 · VCV141780

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.064	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 -0.31	GERP -4.6
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	0.023	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 0.00534% African / African-American · 4/74,920 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00279% 45/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Admixed American	0.00333%	29,992
South Asian	0.00329%	30,363
European (non-Finnish)	0.00263%	38,066
Finnishnot grpmax-eligible	0.00156%	64,034

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.Asn3329Ser
Coding: c.9986A>G
MANE Select: NM_000059
dbSNP: rs76635144
Type: single nucleotide variant
Location: chr13:32398499 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3329: the 'tr2 region' region

Full BRCA2 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, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Asn3329His Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asn3329Ile Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asn3329Asp Uncertain significance ★ ⚠ same residue
BRCA2 p.Asn3329= Likely benign ★ same residue
BRCA2 p.Asn3329fs Conflicting classifications of pathogenicity ★ ⚠ 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-asn3329ser (accessed [today's date]).

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