Is BRCA2 p.Arg2336Pro (c.7007G>C) pathogenic?

BRCA2 p.Arg2336Pro (c.7007G>C) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 21 submitters; last evaluated 2025-07-11). AlphaMissense: likely benign (0.2065); Very rare (popmax 0.000138%); Associated with BRCA2-related disorder.

What condition is associated with BRCA2 p.Arg2336Pro (c.7007G>C)?

BRCA2 p.Arg2336Pro (c.7007G>C) is associated with BRCA2-related disorder, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Arg2336Pro (c.7007G>C) in the general population?

BRCA2 p.Arg2336Pro (c.7007G>C) is very rare (popmax 0.000138%) (gnomAD).

What do computational predictors say about BRCA2 p.Arg2336Pro (c.7007G>C)?

AlphaMissense predicts likely benign (score 0.2065) — an in-silico prediction, not a clinical call.

BRCA2 p.Arg2336Pro

c.7007G>C · rs28897743 · VCV52241

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.2065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000138%)

Conditions

BRCA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.2065	likely benign ⚠ discordant with ClinVar
REVEL	0.425	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Pangolin	Δ0.42	loss · gain 0.02 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	29.0	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 0.000138%

Overall 0.000138% 2/1,450,870 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,434
Remaining individualsnot grpmax-eligible	0.00161%	62,066

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Ovarian Cancer	Rucaparib	C	Sensitivity/Response

Variant & gene context

Gene: BRCA2
Protein: p.Arg2336Pro
Coding: c.7007G>C
MANE Select: NM_000059
dbSNP: rs28897743
Type: single nucleotide variant
Location: chr13:32346896 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2336: a UniProt-annotated variant site (in fancd1; affects protein splicing and expression; decreases homologous recombination-mediated dna repair); a UniProt-annotated variant site (in); the 'interaction with hsf2bp' 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 cancer breast-ovarian cancer, familial, susceptibility to, 1 Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRCA2 p.Arg2336His Pathogenic ★★★ ⚠ same residue
BRCA2 p.Arg2336Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
BRCA2 p.Arg2336= Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Arg2336Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Arg2336Gly Likely benign ★ same residue
BRCA2 p.Arg2336fs Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>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-arg2336pro (accessed [today's date]).

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