Is BARD1 p.Glu740Lys (c.2218G>A) pathogenic?

BARD1 p.Glu740Lys (c.2218G>A) is classified Uncertain significance in BARD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-21). AlphaMissense: likely pathogenic (0.5757); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BARD1 p.Glu740Lys (c.2218G>A)?

BARD1 p.Glu740Lys (c.2218G>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Glu740Lys (c.2218G>A) in the general population?

BARD1 p.Glu740Lys (c.2218G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BARD1 p.Glu740Lys (c.2218G>A)?

AlphaMissense predicts likely pathogenic (score 0.5757) — an in-silico prediction, not a clinical call.

BARD1 p.Glu740Lys

c.2218G>A · rs1692204026 · VCV939803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5757 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5757	likely pathogenic
REVEL	0.216	benign-leaning
SaProt	LLR -11.70	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BARD1
Protein: p.Glu740Lys
Coding: c.2218G>A
MANE Select: NM_000465
dbSNP: rs1692204026
Type: single nucleotide variant
Location: chr2:214728792 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 740: the brct 2 domain

Full BARD1 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

Also linked: hereditary breast carcinoma

Similar variants

BARD1 p.Glu740Ter Likely pathogenic ★ same residue
BARD1 p.Glu740= Likely benign ★ 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
BARD1 c.1396-1G>C Likely pathogenic ★★ same condition
BARD1 c.1396-1G>T Likely pathogenic ★★ same condition
BARD1 c.1396-2A>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-glu740lys (accessed [today's date]).

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