Is BARD1 p.Ser22Phe (c.65C>T) pathogenic?

BARD1 p.Ser22Phe (c.65C>T) is classified Uncertain significance in BARD1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1173); Ultra-rare (popmax 0.0112%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BARD1 p.Ser22Phe (c.65C>T)?

BARD1 p.Ser22Phe (c.65C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BARD1 p.Ser22Phe (c.65C>T) in the general population?

BARD1 p.Ser22Phe (c.65C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about BARD1 p.Ser22Phe (c.65C>T)?

AlphaMissense predicts likely benign (score 0.1173) — an in-silico prediction, not a clinical call.

BARD1 p.Ser22Phe

c.65C>T · rs876659724 · VCV232367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1173 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1173	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -9.12	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 6.8	GERP 0.96, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 81 kb · p 0.077 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0112% East Asian · 5/44,476 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.000499% 8/1,602,366 alleles · ultra-rare exomes 6/1,450,132 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,895
Remaining individualsnot grpmax-eligible	0.00161%	62,004
European (non-Finnish)	0.00017%	588,093

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.Ser22Phe
Coding: c.65C>T
MANE Select: NM_000465
dbSNP: rs876659724
Type: single nucleotide variant
Location: chr2:214809505 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.82 · 11 PDB
Residue 22: the 'disordered' region

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.Ser22Thr Uncertain significance ★ ⚠ same residue
BARD1 p.Ser22Tyr Uncertain significance ★ ⚠ same residue
BARD1 p.Ser22= 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

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-ser22phe (accessed [today's date]).

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