Is BARD1 p.Ala594Pro (c.1780G>C) pathogenic?

BARD1 p.Ala594Pro (c.1780G>C) is classified Uncertain significance in BARD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.8519); Very rare (popmax 0.00223%, eas); Associated with Hereditary cancer.

What condition is associated with BARD1 p.Ala594Pro (c.1780G>C)?

BARD1 p.Ala594Pro (c.1780G>C) is associated with Hereditary cancer (ClinVar).

How common is BARD1 p.Ala594Pro (c.1780G>C) in the general population?

BARD1 p.Ala594Pro (c.1780G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BARD1 p.Ala594Pro (c.1780G>C)?

AlphaMissense predicts likely pathogenic (score 0.8519) — an in-silico prediction, not a clinical call.

BARD1 p.Ala594Pro

c.1780G>C · VCV3338487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.8519	likely pathogenic · top 9% in BARD1
REVEL	0.748	pathogenic-leaning
SaProt	LLR -15.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,838 alleles

Overall 6.84e-05% 1/1,461,790 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.Ala594Pro
Coding: c.1780G>C
MANE Select: NM_000465
Type: single nucleotide variant
Location: chr2:214745752 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 594: the brct 1 domain

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

Disease context

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BARD1 p.Ala594Gly Uncertain significance ★★ ⚠ same residue
BARD1 p.Ala594Ser Uncertain significance ★★ ⚠ same residue
BARD1 p.Ala594Asp Uncertain significance ★ ⚠ same residue
BARD1 p.Ala594Thr Uncertain significance ★ ⚠ same residue
BARD1 p.Asn488Ser Uncertain significance ★★ ⚠ same condition
BARD1 p.Lys139Glu Uncertain significance ★★ ⚠ same condition
BARD1 p.Arg658Cys Benign/Likely benign ★★ ⚠ same condition
BARD1 c.2002-12T>G Conflicting classifications of pathogenicity ★ 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-ala594pro (accessed [today's date]).

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