# NM_004874.4(BAG4):c.558G>T (p.Trp186Cys)

https://sugi.bio/variant/bag4-p-trp186cys

## Summary

**BAG4 p.Trp186Cys (c.558G>T)** is classified **Uncertain significance** in BAG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.8037); Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs372261481 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the BAG4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [BAG4](https://sugi.bio/atlas/gene/BAG4/) |
| Protein change (HGVS p.) | p.Trp186Cys |
| Coding change (HGVS c.) | c.558G>T |
| MANE Select transcript | [NM_004874](https://www.ncbi.nlm.nih.gov/nuccore/NM_004874) |
| dbSNP | [rs372261481](https://www.ncbi.nlm.nih.gov/snp/rs372261481/) |
| Variant type | single nucleotide variant |
| Location | chr8:38207691-38207691 (GRCh38) |
| ClinVar | [VCV2489043](https://www.ncbi.nlm.nih.gov/clinvar/variation/2489043/) |

**All HGVS expressions:** `NC_000008.10:g.38065209G>T`, `NC_000008.11:g.38207691G>T`, `NM_001204878.2:c.450G>T`, `NM_004874.4:c.558G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8037)
- REVEL 0.664 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.177 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.689, GERP 1.98, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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.*
- Regional missense constraint: **o/e 1.08** across the covering region of the MANE Select transcript (38,176,870–38,207,749), spanning 30,879 bp. Chi-square p 0.2. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**.
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,004 in the highest group · 2/1,614,036 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**BAG4** population constraint: LOEUF 0.704, pLI 0.0013182, missense-Z 0.77712. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **186** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 55.41, 18% of residues very-high.

**2 experimental structure(s)** (PDB): [1M62](https://www.rcsb.org/structure/1M62), [1M7K](https://www.rcsb.org/structure/1M7K).

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

*Describes the biological roles of BAG4 (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:** BAG4's established molecular role includes RNA binding. p.Trp186Cys falls in the disordered region. In Reactome, BAG4 is annotated in disease pathway(s) including **Signaling by FGFR1 in disease**, **Signaling by plasma membrane FGFR1 fusions**.

**Disease mechanism (Reactome):** BAG4 loss or alteration is curated in [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302), [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336).

### Pathways affected {#pathways}

BAG4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [TNF signaling](https://reactome.org/content/detail/R-HSA-75893) | curated |

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

**Molecular function:** RNA binding, ubiquitin protein ligase binding.

**Biological process:** cellular response to tumor necrosis factor, obsolete negative regulation of protein targeting to mitochondrion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-29 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BAG4 variant pages (same residue, condition, or type): [BAG4 p.Ala107Val](/variant/bag4-p-ala107val), [BAG4 p.Ala157Val](/variant/bag4-p-ala157val), [BAG4 p.Ala248Thr](/variant/bag4-p-ala248thr), [BAG4 p.Ala447Val](/variant/bag4-p-ala447val), [BAG4 p.Arg185His](/variant/bag4-p-arg185his), [BAG4 p.Arg311Trp](/variant/bag4-p-arg311trp), [BAG4 p.Arg40Leu](/variant/bag4-p-arg40leu), [BAG4 p.Arg51Gln](/variant/bag4-p-arg51gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2489043). 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.*