BAG3

Chr 10AD

BAG cochaperone 3

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

NCBI Gene: 9531 ENSG00000151929 UniProt: O95817 OMIM: 603883

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.454 OMIM phenotypes

Clinical Summary— BAG3

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Gene-Disease Validity (ClinGen)

myofibrillar myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.

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ClinVar Variants

59 unique Pathogenic / Likely Pathogenic· 303 VUS of 500 total submissions

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — BAG3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE0.20 (0.10–0.45)

0≤0.351.4

Missense OE1.11 (1.02–1.21)

0≤0.61.4

Synonymous OE1.01

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBAG3-related myofibrillar myopathyOTHERAD

definitiveBAG3-related dilated cardiomyopathyOTHERAD

0.4389th %ile

GOF

0.4183th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 83% of P/LP variants are LoF · LOEUF 0.45

GOF1 literature citation

Literature Evidence

GOFMutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues.PMID:30559338

LOFGenome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathyPMID:21353195

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44

Likely Pathogenic15

VUS303

Likely Benign123

Benign3

Conflicting6

Pathogenic

Likely Pathogenic

303

VUS

123

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	1	8	0	44
Likely Pathogenic	14	0	1	0	15
VUS	14	275	14	0	303
Likely Benign	0	2	18	103	123
Benign	0	0	3	0	3
Conflicting	—				6
Total	63	278	44	103	494

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in 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.

3D Protein StructureAlphaFold

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

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GeneReview available — BAG3

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Dilated Cardiomyopathy (DCM)BAG3 Mutation Associated Dilated Cardiomyopathy

An AAV Gene Therapy Trial of AFTX-201 in Adults With BAG3-Associated Dilated Cardiomyopathy (DCM)

NOT YET RECRUITING

NCT07426419Phase PHASE1, PHASE2Affinia TherapeuticsStarted 2026-03

AFTX-201

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)

BAG3 Mutation Associated Dilated Cardiomyopathy

ALXN2350 in Adult Participants With BAG3-Associated Dilated Cardiomyopathy

RECRUITING

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