BAG3

Chr 10AD

BAG cochaperone 3

NCBI Gene: 9531ENSG00000151929UniProt: O95817

Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g. HSPA1A/HSP70 or HSPA8/HSC70, and small heat shock proteins (sHSPs), e.g. HSPB8 (PubMed:27884606, PubMed:30559338). Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from HSP70s, thereby triggering client protein release (PubMed:27884606, PubMed:30559338). Nucleotide release is mediated via BAG3 binding to the nucleotide-binding domain (NBD) of HSP70s, whereas client release is mediated via binding to the substrate-binding domain (SBD) (PubMed:27474739, PubMed:9873016). Has anti-apoptotic activity (PubMed:10597216). Plays a role in the HSF1 nucleocytoplasmic transport (PubMed:26159920)

Primary Disease Associations & Inheritance

?Neuronopathy, distal hereditary motor, autosomal dominant 15MIM #621094
AD
Cardiomyopathy, dilated, 1HHMIM #613881
AD
Charcot-Marie-Tooth disease, axonal, type 2JJMIM #621095
AD
Myopathy, myofibrillar, 6MIM #612954
AD
694
ClinVar variants
79
Pathogenic / LP
0.62
pLI score
5
Active trials
Clinical Summary— BAG3
🧬
Gene-Disease Validity (ClinGen)
myofibrillar myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
79 Pathogenic / Likely Pathogenic· 413 VUS of 694 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.74Z-score
OE missense 1.11 (1.02–1.21)
376 obs / 337.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.10–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.02–1.21)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 4 / 20.5Missense obs/exp: 376 / 337.9Syn Z: -0.13

ClinVar Variant Classifications

694 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic19
VUS413
Likely Benign187
Benign3
Conflicting12
60
Pathogenic
19
Likely Pathogenic
413
VUS
187
Likely Benign
3
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
1
26
0
60
Likely Pathogenic
14
0
5
0
19
VUS
11
374
27
1
413
Likely Benign
0
4
22
161
187
Benign
0
0
3
0
3
Conflicting
—12
Total5837983162694

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.

Gene2Phenotype Curations

BAG3-related myofibrillar myopathy

definitive
ADUndeterminedAltered Gene Product Structure
Cardiac
G2P ↗
missense variant

BAG3-related dilated cardiomyopathy

definitive
ADUndeterminedAltered Gene Product Structure, Decreased Gene Product Level
Cardiac
G2P ↗
splice acceptor variantsplice donor variantframeshift variantmissense variantstop gained NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
BAG COCHAPERONE 3; BAG3
MIM #603883 · *

?Neuronopathy, distal hereditary motor, autosomal dominant 15

MIM #621094

Molecular basis of disorder known

Autosomal dominant

Cardiomyopathy, dilated, 1HH

MIM #613881

Molecular basis of disorder known

Autosomal dominant

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

MIM #621095

Molecular basis of disorder known

Autosomal dominant

Myopathy, myofibrillar, 6

MIM #612954

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — BAG3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.
Mazzarotto F et al.·Circulation
2020
Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
Jordan E et al.·Circulation
2021
Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.
Goli R et al.·Circulation
2021
Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration.
Rusmini P et al.·Autophagy
2019Functional
Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments.
Orphanou N et al.·Heart Fail Rev
2022Review
Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.
Wang BZ et al.·J Clin Invest
2025
Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum.
Lee DSM et al.·Nat Genet
2025
Myofibrillar myopathies.
Selcen D·Neuromuscul Disord
2011Review
Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.
de Frutos F et al.·Eur Heart J Cardiovasc Imaging
2023
Myofibrillar myopathies.
Selcen D·Curr Opin Neurol
2010Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
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
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
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)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
Dilated Cardiomyopathy (DCM)

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

NOT YET 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)

External Resources

Links to major genomics databases and tools