Is BRCA2 p.Asp128Gly (c.383A>G) pathogenic?

BRCA2 p.Asp128Gly (c.383A>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Asp128Gly (c.383A>G)?

BRCA2 p.Asp128Gly (c.383A>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Asp128Gly (c.383A>G) in the general population?

BRCA2 p.Asp128Gly (c.383A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Asp128Gly (c.383A>G)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

BRCA2 p.Asp128Gly

c.383A>G · rs80358627 · VCV51538

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.246	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.39	donor gain, 1 bp away · raw score · deltas
Pangolin	Δ0.41	gain · loss 0.27 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.002	GERP -4.3
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	14.43	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 0.00223% East Asian · 1/44,828 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000373% 6/1,608,444 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,828
Admixed American	0.00167%	59,992
South Asian	0.0011%	90,956
European (non-Finnish)	0.000255%	391,710

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.Asp128Gly
Coding: c.383A>G
MANE Select: NM_000059
dbSNP: rs80358627
Type: single nucleotide variant
Location: chr13:32325142 (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 breast-ovarian cancer, familial, susceptibility to, 2 hereditary breast carcinoma

Similar variants

BRCA2 p.Asp128Val Uncertain significance ★★ ⚠ same residue
BRCA2 p.Asp128His Uncertain significance ★ ⚠ same residue
BRCA2 p.Asp128fs Pathogenic ★ same residue
BRCA2 p.Asp128Ala 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
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-asp128gly (accessed [today's date]).

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