# NM_004281.4(BAG3):c.252_258dup (p.Pro87fs)

https://sugi.bio/variant/bag3-p-pro87fs

## Summary

**BAG3 p.Pro87fs (c.252_258dup)** is classified **Pathogenic** in BAG3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-23). No gnomAD frequency available for this variant; Associated with dilated cardiomyopathy 1HH.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1564773559 · 3 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BAG3 gene that is considered disease-causing, submitted by 3 submitters, and is linked to dilated cardiomyopathy 1HH.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | BAG3 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015726/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BAG3](https://sugi.bio/atlas/gene/BAG3/) |
| Protein change (HGVS p.) | p.Pro87fs |
| Coding change (HGVS c.) | c.252_258dup |
| MANE Select transcript | [NM_004281](https://www.ncbi.nlm.nih.gov/nuccore/NM_004281) |
| dbSNP | [rs1564773559](https://www.ncbi.nlm.nih.gov/snp/rs1564773559/) |
| Variant type | Duplication |
| Location | chr10:119669920-119669921 (GRCh38) |
| ClinVar | [VCV560609](https://www.ncbi.nlm.nih.gov/clinvar/variation/560609/) |

**All HGVS expressions:** `LRG_742:g.23553_23559dup`, `LRG_742t1:c.252_258dup`, `NC_000010.10:g.121429434_121429440dup`, `NC_000010.11:g.119669922_119669928dup`, `NG_016125.1:g.23553_23559dup`, `NM_004281.3:c.252_258dupTGTGTAC`, `NM_004281.4:c.252_258dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.86, GERP -3.93 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.538, pLI 0.92034), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BAG3** population constraint: LOEUF 0.538, pLI 0.92034, missense-Z -0.061263; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dilated cardiomyopathy 1HH** — Definitive (AD)
- **myofibrillar myopathy** — Definitive (AD)

## Protein context {#protein}

Residue **87** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 57.98, 19% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of BAG3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BAG3's established molecular role includes adenyl-nucleotide exchange factor activity. p.Pro87fs falls in the disordered region.


### Pathways affected {#pathways}

BAG3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** adenyl-nucleotide exchange factor activity, protein-macromolecule adaptor activity, cadherin binding, protein-folding chaperone binding.

**Biological process:** protein folding, extrinsic apoptotic signaling pathway via death domain receptors, negative regulation of striated muscle cell apoptotic process, cellular response to heat, cellular response to unfolded protein, positive regulation of protein import into nucleus.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-23.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2017-03-31 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-23 |

## Associated conditions {#conditions}

[dilated cardiomyopathy 1HH](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1hh/), [dilated cardiomyopathy](https://sugi.bio/atlas/disease/dilated-cardiomyopathy/), [myofibrillar myopathy 6](https://sugi.bio/atlas/disease/myofibrillar-myopathy-6/).

**Reported phenotype names (ClinVar):** Dilated cardiomyopathy 1HH, Primary dilated cardiomyopathy, Cardiovascular phenotype, Myofibrillar myopathy 6, Dilated Cardiomyopathy.

## Similar variants {#similar}

Related BAG3 variant pages (same residue, condition, or type): [BAG3 p.Pro87=](/variant/bag3-p-pro87), [BAG3 p.Pro87Ser](/variant/bag3-p-pro87ser), [BAG3 p.Arg203fs](/variant/bag3-p-arg203fs), [BAG3 p.Leu287fs](/variant/bag3-p-leu287fs), [BAG3 p.Ser70fs](/variant/bag3-p-ser70fs), [BAG3 p.Val432fs](/variant/bag3-p-val432fs), [BAG3 p.Ala556fs](/variant/bag3-p-ala556fs), [BAG3 p.Asp544_Pro552dup](/variant/bag3-p-asp544-pro552dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 560609). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*