# NM_004281.4(BAG3):c.549C>G (p.Ser183=)

https://sugi.bio/variant/bag3-p-ser183

## Summary

**BAG3 p.Ser183= (c.549C>G)** is classified **Conflicting classifications of pathogenicity** in BAG3 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-02-04). Rare (popmax 0.191%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs112929734 · 18 submitters · 4 linked conditions · rare (popmax 0.191%, nfe)

## For patients & families {#patients}

This is a change in the BAG3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 18 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [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.Ser183= |
| Coding change (HGVS c.) | c.549C>G |
| MANE Select transcript | [NM_004281](https://www.ncbi.nlm.nih.gov/nuccore/NM_004281) |
| dbSNP | [rs112929734](https://www.ncbi.nlm.nih.gov/snp/rs112929734/) |
| Variant type | single nucleotide variant |
| Location | chr10:119672296-119672296 (GRCh38) |
| ClinVar | [VCV136493](https://www.ncbi.nlm.nih.gov/clinvar/variation/136493/) |

**All HGVS expressions:** `LRG_742:g.25927C>G`, `LRG_742t1:c.549C>G`, `NC_000010.10:g.121431808C>G`, `NC_000010.11:g.119672296C>G`, `NG_016125.1:g.25927C>G`, `NM_004281.4:c.549C>G`

## 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 -3.574, GERP -4.88 — fast-evolving / accelerated position
- CADD: **PHRED 0.983**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.191%** (nfe) · FAF95 0.184% · FAF99 0.181% · 2,250/1,179,968 in the highest group · 2,455/1,613,910 alleles overall — rare (popmax 0.191%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.191% | 524 |
| South Asian | 0.111% | 902 |
| Remaining individuals (not grpmax-eligible) | 0.0736% | 1,359 |
| African / African-American | 0.0413% | 2,421 |
| Finnish (not grpmax-eligible) | 0.0251% | 3,990 |
| Admixed American | 0.015% | 6,670 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,803 |

*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 **183** 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.Ser183= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (9 Benign, 9 Likely benign, 1 Uncertain significance).

**Submission history:** 19 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-04-21 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2016-07-01 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Benign | criteria provided, single submitter | clinical testing | 2023-02-24 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-08-12 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2020-10-31 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-05-21 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, Dilated cardiomyopathy 1HH, Myofibrillar myopathy 6, not provided, Cardiomyopathy, AllHighlyPenetrant, none provided, Cardiomyopathies.

## Similar variants {#similar}

Related BAG3 variant pages (same residue, condition, or type): [BAG3 p.Ser183Pro](/variant/bag3-p-ser183pro), [BAG3 p.Arg121Ter](/variant/bag3-p-arg121ter), [BAG3 p.Arg123Ter](/variant/bag3-p-arg123ter), [BAG3 p.Arg309Ter](/variant/bag3-p-arg309ter), [BAG3 p.Arg473Ter](/variant/bag3-p-arg473ter), [BAG3 p.Arg90Ter](/variant/bag3-p-arg90ter), [BAG3 p.Gln132Ter](/variant/bag3-p-gln132ter), [BAG3 p.Gln135Ter](/variant/bag3-p-gln135ter).

### 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 136493). 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.*