Is BARD1 p.Arg43Ser (c.127C>A) pathogenic?

BARD1 p.Arg43Ser (c.127C>A) is classified Uncertain significance in BARD1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.3932); Ultra-rare (popmax 0.0156%, eas); Associated with BARD1-related disorder.

What condition is associated with BARD1 p.Arg43Ser (c.127C>A)?

BARD1 p.Arg43Ser (c.127C>A) is associated with BARD1-related disorder, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Arg43Ser (c.127C>A) in the general population?

BARD1 p.Arg43Ser (c.127C>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about BARD1 p.Arg43Ser (c.127C>A)?

AlphaMissense predicts ambiguous (score 0.3932) — an in-silico prediction, not a clinical call.

BARD1 p.Arg43Ser

c.127C>A · rs752871324 · VCV220225

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

BARD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3932	ambiguous
REVEL	0.281	benign-leaning
SaProt	LLR -5.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	23.8	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 0.0156% East Asian · 7/44,822 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000558% 9/1,611,782 alleles · ultra-rare exomes 7/1,459,596 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,403
Remaining individualsnot grpmax-eligible	0.00321%	31,198

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.Arg43Ser
Coding: c.127C>A
MANE Select: NM_000465
dbSNP: rs752871324
Type: single nucleotide variant
Location: chr2:214809443 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 43: an α-helix; the 'interaction with brca1' region

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

Disease context

BARD1-related disorder

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma BARD1-related cancer predisposition

Similar variants

BARD1 p.Arg43Cys Uncertain significance ★★ ⚠ same residue
BARD1 p.Arg43Gly Uncertain significance ★★ ⚠ same residue
BARD1 p.Arg43His Uncertain significance ★★ ⚠ same residue
BARD1 p.Arg43Leu Uncertain significance ★★ ⚠ same residue
BARD1 p.Arg43Pro 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-arg43ser (accessed [today's date]).

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