Is BAG3 p.Ile94Phe (c.280A>T) pathogenic?

BAG3 p.Ile94Phe (c.280A>T) is classified Conflicting classifications of pathogenicity in BAG3 (ClinVar, Conflicting submitters, 23 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.6288); Rare (popmax 0.126%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with BAG3 p.Ile94Phe (c.280A>T)?

BAG3 p.Ile94Phe (c.280A>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy, myofibrillar myopathy 6 (ClinVar).

How common is BAG3 p.Ile94Phe (c.280A>T) in the general population?

BAG3 p.Ile94Phe (c.280A>T) is rare (popmax 0.126%, nfe) (gnomAD).

What do computational predictors say about BAG3 p.Ile94Phe (c.280A>T)?

AlphaMissense predicts likely pathogenic (score 0.6288) — an in-silico prediction, not a clinical call.

BAG3 p.Ile94Phe

c.280A>T · rs145393807 · VCV178007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 23 submitters

AlphaMissense

likely pathogenic

0.6288 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.126%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6288	likely pathogenic
REVEL	0.646	pathogenic-leaning
SaProt	LLR -12.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	24.6	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 0.126% European (non-Finnish) · 1,485/1,180,032 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.0974% 1,573/1,614,222 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.877%	114
European (non-Finnish)grpmax	0.126%	795
Remaining individualsnot grpmax-eligible	0.056%	1,786
Finnishnot grpmax-eligible	0.0219%	4,575
African / African-American	0.02%	5,004
Admixed American	0.0183%	5,457
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,922

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BAG3
Protein: p.Ile94Phe
Coding: c.280A>T
MANE Select: NM_004281
dbSNP: rs145393807
Type: single nucleotide variant
Location: chr10:119669950 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.92 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.98
Residue 94: a UniProt-annotated variant site (in)

Full BAG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy myofibrillar myopathy 6 dilated cardiomyopathy 1HH

Similar variants

BAG3 p.Ile94Val Uncertain significance ★★ ⚠ same residue
BAG3 p.Arg121Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg123Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg309Ter Pathogenic ★★ same condition
BAG3 p.Arg473Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg90Ter Pathogenic ★★ same condition
BAG3 p.Gln132Ter Pathogenic ★★ same condition
BAG3 p.Gln135Ter 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/bag3-p-ile94phe (accessed [today's date]).

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