Is BARD1 p.Ala222Val (c.665C>T) pathogenic?

BARD1 p.Ala222Val (c.665C>T) is classified Conflicting classifications of pathogenicity in BARD1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0832); Ultra-rare (popmax 0.0131%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BARD1 p.Ala222Val (c.665C>T)?

BARD1 p.Ala222Val (c.665C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Ala222Val (c.665C>T) in the general population?

BARD1 p.Ala222Val (c.665C>T) is ultra-rare (popmax 0.0131%, amr) (gnomAD).

What do computational predictors say about BARD1 p.Ala222Val (c.665C>T)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

BARD1 p.Ala222Val

c.665C>T · rs142086060 · VCV460758

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -1.4
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	11.28	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 0.0131% Admixed American · 7/53,478 alleles

Filtering AF 0.00612% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00428%

Overall 0.000691% 11/1,591,562 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0131%	7,640
African / African-American	0.00547%	18,286

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.Ala222Val
Coding: c.665C>T
MANE Select: NM_000465
dbSNP: rs142086060
Type: single nucleotide variant
Location: chr2:214781209 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB

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.Ala222Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BARD1 p.Ala222Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala222val (accessed [today's date]).

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