# WFS1 Wolframin — R375S Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Arginine → Serine at position 375. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.625, DynaMut2 ΔΔG -1.19 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R375S (p.Arginine375Serine) |
| **DNA change** | c.1123C>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV004744072 |
| **Amino acid change** | Arginine (R) → Serine (S) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 375** | **83.00** — well-folded |
| **Domain** | Transmembrane helix 3 |
| **Position context** | Inside Transmembrane helix 3 · position 375 is bilayer-embedded |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 375 sits in a transmembrane helix (Transmembrane helix 3). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6248** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.19 (Destabilising)** |
| Job ID | 178092130195 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092130195 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2026/01/12 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | R375S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

(no conditions catalogued)

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## Research Path Decision Tree

```
ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking
```

## Final Schema Categorization

**Category 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.19 < 2 kcal/mol (fold intact) + AlphaMissense 0.625 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

**Why this card matters.** Wolframin's fold survives this substitution (|ΔΔG|=1.19 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.625. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R375S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 375 with ball-and-stick + neighbors within 5Å)
- `R375S_variant_card.md` — this card (source of truth)
- `R375S_variant_card.html` — styled printable card
- `R375S_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `R375S_wildtype_interactions.pse` / `R375S_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*