BAG3

Chr 10

BAG cochaperone 3

Also known as: BAG-3, BIS, CAIR-1, CMD1HH, CMT2JJ, HMND15, MFM6

NCBI Gene: 9531 ENSG00000151929 UniProt: O95817

BAG3 encodes a co-chaperone protein that binds to the Hsc70 ATPase domain and inhibits its chaperone activity by promoting substrate release. Autosomal dominant mutations cause a spectrum of neuromuscular disorders including distal hereditary motor neuropathy, axonal Charcot-Marie-Tooth disease, myofibrillar myopathy, and dilated cardiomyopathy. The pathogenic mechanism involves disruption of protein quality control through impaired chaperone-mediated protein folding and degradation.

ResearchSummary from RefSeq, OMIM, UniProt

BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMyopathy, myofibrillar, 6

UniProtCardiomyopathy, dilated, 1HH

UniProtNeuronopathy, distal hereditary motor, autosomal dominant 15

UniProtCharcot-Marie-Tooth disease, axonal, type 2JJ

Clinical highlights

Gene-disease validity (ClinGen)

myofibrillar myopathy · ADDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

144

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.617

Z-score 3.37

OE 0.20 (0.10–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.74Z-score

OE missense 1.11 (1.02–1.21)

376 obs / 337.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.20 (0.10–0.45)

0≤0.351.4

Missense OE?1.11 (1.02–1.21)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 20.5Missense obs/exp: 376 / 337.9Syn Z: -0.13

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

BAG3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

BAG3 Mutation Associated Dilated Cardiomyopathy

ALXN2350 in Adult Participants With BAG3-Associated Dilated Cardiomyopathy

RECRUITING

NCT07218887Phase PHASE1, PHASE2Alexion Pharmaceuticals, Inc.Started 2025-10-24

ALXN2350

Dilated Cardiomyopathy

Observational Study of Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults

NOT YET RECRUITING

NCT07646600AstraZenecaStarted 2026-06-29

Observational, None intervention

Arrhythmogenic Cardiomyopathies

Tissue and Metabolic Characterization of Arrhythmogenic Cardiomyopathies by Hybrid PET-MRI Imaging, Impact of the Observed Profiles on the Phenotype and on the Evolution of Cardiomyopathy

RECRUITING

NCT05450783Nantes University HospitalStarted 2022-09-01

Biocollection

Dilated Cardiomyopathy (DCM)

A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy

RECRUITING

NCT07137338Phase PHASE1Rocket Pharmaceuticals Inc.Started 2026-06

RP-A701 is a recombinant viral vector composed of an AAV serotype rh.74 (AAVrh.74) capsid encapsulating the transgene, BCL2-associated Athanogene 3 (BAG3)

Cardiomyopathy, DilatedBcl-2 Anathogene-3 (BAG3) Dilated Cardiomyopathy (DCM)

A Study About the Natural History in Adults With BAG3 Dilated Cardiomyopathy (a Type of Heart Disease) (BAG3 DCM)

ACTIVE NOT RECRUITING

NCT05981092Alexion Pharmaceuticals, Inc.Started 2022-10-14