Is BARD1 p.Arg658Pro (c.1973G>C) pathogenic?

BARD1 p.Arg658Pro (c.1973G>C) is classified Uncertain significance in BARD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-28). AlphaMissense: likely benign (0.2326); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with BARD1 p.Arg658Pro (c.1973G>C)?

BARD1 p.Arg658Pro (c.1973G>C) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is BARD1 p.Arg658Pro (c.1973G>C) in the general population?

BARD1 p.Arg658Pro (c.1973G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BARD1 p.Arg658Pro (c.1973G>C)?

AlphaMissense predicts likely benign (score 0.2326) — an in-silico prediction, not a clinical call.

BARD1 p.Arg658Pro

c.1973G>C · rs377227840 · VCV530204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.2326	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -12.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.96	GERP -3.9
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	19.31	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 8.48e-05% European (non-Finnish) · 1/1,179,798 alleles

Overall 6.84e-05% 1/1,461,570 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: BARD1
Protein: p.Arg658Pro
Coding: c.1973G>C
MANE Select: NM_000465
dbSNP: rs377227840
Type: single nucleotide variant
Location: chr2:214730439 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 658: a UniProt-annotated variant site (in); an α-helix

Full BARD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BARD1 p.Arg658Gly Uncertain significance ★★ ⚠ same residue
BARD1 p.Arg658= Benign/Likely benign ★★ same residue
BARD1 p.Arg658Cys Benign/Likely benign ★★ ⚠ same residue
BARD1 p.Arg658His Conflicting classifications of pathogenicity ★ ⚠ same residue
BARD1 p.Arg658Leu Uncertain significance ★ ⚠ same residue
BARD1 c.1314+1G>A Pathogenic/Likely pathogenic ★★ same condition
BARD1 c.1314+1G>T Likely pathogenic ★★ same condition
BARD1 c.1396-1G>A Likely 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/bard1-p-arg658pro (accessed [today's date]).

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