# WFS1 Wolframin — R457S Variant Card

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

*Arginine → Serine at position 457 in connecting loop. ClinVar Conflicting including monogenic diabetes + spastic. AlphaMissense 0.515 (borderline), ΔΔG -0.82.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R457S (p.Arginine457Serine) |
| **DNA change** | c.1371G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215389 |
| **Amino acid change** | Arginine (R) → Serine (S) — long positively-charged amine replaced by small polar hydroxyl. Loss of charge + side-chain length. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 457** | **88.25** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 457 (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Natural variant: 457-457 in WFS1; dbSNP:rs113446173

> Position 457 in connecting loop. Neighbors: ALA458 (2.5 Å), ARG456 (2.5 Å — adjacent existing arginine!), TYR454 (3.7 Å), PRO453 (4.1 Å).

Replacing R457 with serine eliminates one of two adjacent arginines (R456 + R457). The local positively-charged surface character is reduced. ΔΔG 0.82 + AM 0.515 borderline + monogenic diabetes confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5153** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.82 (Destabilising)** |
| Job ID | 177992469629 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992469629 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/18 00:00 |
| Inheritance | Monogenic diabetes + WFS1 spectrum. |
| WFS1 variant landscape | R457S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-related disorder
- Monogenic diabetes
- Spastic ataxia

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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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.82. AlphaMissense 0.515 borderline + multi-phenotype confirm severe consequence.<br/><br/>Mechanism: loss of R457 charge from R456-R457 cluster. Therapeutic: site-directed at the loop's charged surface.

**Why this card matters.** R457S continues the charge-loss class in connecting loops.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R457S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 457 with ball-and-stick + neighbors within 5Å)
- `R457S_variant_card.md` — this card (source of truth)
- `R457S_variant_card.html` — styled printable card
- `R457S_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)
- `R457S_wildtype_interactions.pse` / `R457S_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.*