Is BRCA2 p.Asn3221Thr (c.9662A>C) pathogenic?

BRCA2 p.Asn3221Thr (c.9662A>C) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0722); Very rare (popmax 0.000679%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Asn3221Thr (c.9662A>C)?

BRCA2 p.Asn3221Thr (c.9662A>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Asn3221Thr (c.9662A>C) in the general population?

BRCA2 p.Asn3221Thr (c.9662A>C) is very rare (popmax 0.000679%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Asn3221Thr (c.9662A>C)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

BRCA2 p.Asn3221Thr

c.9662A>C · rs1476681505 · VCV531385

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000679%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.287	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.047	GERP -4.3
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	1.885	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000679% European (non-Finnish) · 8/1,177,658 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000549% 8/1,457,292 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.Asn3221Thr
Coding: c.9662A>C
MANE Select: NM_000059
dbSNP: rs1476681505
Type: single nucleotide variant
Location: chr13:32398175 (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

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Asn3221His Uncertain significance ★ ⚠ same residue
BRCA2 p.Asn3221= Likely benign ★ 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
BRCA2 c.475+1G>A Pathogenic ★★★ same condition
BRCA2 c.475+1G>T 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-asn3221thr (accessed [today's date]).

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