Is BRCA2 p.Cys19Phe (c.56G>T) pathogenic?

BRCA2 p.Cys19Phe (c.56G>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-09). AlphaMissense: likely pathogenic (0.5846); Very rare (popmax 0.00329%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Cys19Phe (c.56G>T)?

BRCA2 p.Cys19Phe (c.56G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Cys19Phe (c.56G>T) in the general population?

BRCA2 p.Cys19Phe (c.56G>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Cys19Phe (c.56G>T)?

AlphaMissense predicts likely pathogenic (score 0.5846) — an in-silico prediction, not a clinical call.

BRCA2 p.Cys19Phe

c.56G>T · rs1370260227 · VCV491295

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5846	likely pathogenic · top 7% in BRCA2
REVEL	0.247	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 9.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	24.9	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 0.00329% South Asian · 3/91,074 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,613,630 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.Cys19Phe
Coding: c.56G>T
MANE Select: NM_000059
dbSNP: rs1370260227
Type: single nucleotide variant
Location: chr13:32316516 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 19: the 'interaction with palb2' region

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

Similar variants

BRCA2 p.Cys19= Likely benign ★★★ same residue
BRCA2 p.Cys19Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Cys19Tyr Uncertain significance ★★ ⚠ same residue
BRCA2 p.Cys19Ser 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-cys19phe (accessed [today's date]).

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