Is BARD1 p.Cys53Ser (c.157T>A) pathogenic?

BARD1 p.Cys53Ser (c.157T>A) is classified Uncertain significance in BARD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-25). AlphaMissense: likely pathogenic (0.9576); Very rare (popmax 0.00017%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with BARD1 p.Cys53Ser (c.157T>A)?

BARD1 p.Cys53Ser (c.157T>A) is associated with hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Cys53Ser (c.157T>A) in the general population?

BARD1 p.Cys53Ser (c.157T>A) is very rare (popmax 0.00017%, 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.Cys53Ser (c.157T>A)?

AlphaMissense predicts likely pathogenic (score 0.9576) — an in-silico prediction, not a clinical call.

BARD1 p.Cys53Ser

c.157T>A · rs1354779388 · VCV1507529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.9576	likely pathogenic · top 3% in BARD1
REVEL	0.727	pathogenic-leaning
SaProt	LLR -14.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.63	donor gain · deltas
Pangolin	Δ0.43	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	33.0	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 0.00017% European (non-Finnish) · 2/1,179,828 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,278 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.Cys53Ser
Coding: c.157T>A
MANE Select: NM_000465
dbSNP: rs1354779388
Type: single nucleotide variant
Location: chr2:214809413 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 53: a turn; the 'interaction with brca1' region

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

For Hereditary breast cancer (Orphanet):

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

Similar variants

BARD1 p.Cys53Gly Uncertain significance ★★ ⚠ same residue
BARD1 p.Cys53= Conflicting classifications of pathogenicity ★ same residue
BARD1 p.Cys53Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
BARD1 p.Cys53Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
BARD1 p.Cys53fs Pathogenic/Likely pathogenic ★★ same residue
BARD1 c.1314+1G>A Pathogenic/Likely pathogenic ★★ same condition
BARD1 c.1396-1G>A Likely pathogenic ★★ same condition
BARD1 c.1396-1G>C 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-cys53ser (accessed [today's date]).

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