# WFS1 Wolframin — R708C Variant Card

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

*Arginine → Cysteine at position 708. ClinVar Conflicting (monogenic diabetes, inborn genetic diseases, retinal). AlphaMissense 0.973, ΔΔG -0.36. R→C charge loss + free thiol in ER lumen.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R708C (p.Arginine708Cysteine) |
| **DNA change** | c.2122C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000285046 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — long positively-charged guanidinium replaced by short thiol-bearing residue. Loss of charge plus introduction of potential aberrant disulfide site. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 708** | **93.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 708 (pLDDT 93). Same position as R708L (Atlas card). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 708-708 in dbSNP:rs200099217

> Position 708 sits in the lumenal domain. Neighbors: VAL709 (2.4 Å), VAL707 (2.5 Å — partner of V707F), GLU776 (3.8 Å — likely wild-type salt-bridge partner).

R708C is the second pathogenic substitution at position 708 (with R708L). The mechanism overlaps but differs: R708L removes the charge cleanly with hydrophobic replacement; R708C removes the charge AND introduces a free thiol into the oxidizing ER lumen. The new C708 could engage in aberrant disulfide formation with nearby cysteines, creating misfolding pressure that DynaMut2's |ΔΔG| of 0.36 does not capture.

AlphaMissense 0.973 + monogenic diabetes + retinal phenotype confirm severe functional consequence across tissues.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9734** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.36 (Destabilising)** |
| Job ID | 177992300171 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992300171 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/01 00:00 |
| Inheritance | Multi-phenotype: monogenic diabetes, inborn genetic diseases, retinal involvement. |
| WFS1 variant landscape | R708C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- Inborn genetic diseases
- Retinal involvement

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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> |ΔΔG| = 0.36 — fold survives. AlphaMissense 0.973 + multi-tissue phenotype confirm severe consequence.<br/><br/>Mechanism: loss of R708-E776 salt bridge plus free-thiol misfolding pressure. Therapeutic: site-directed at the E776 microregion, with attention to oxidative chemistry risk.

**Why this card matters.** R708C + R708L + V707F at adjacent positions form a multi-variant target cluster at the R708-E776 long-range salt-bridge region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R708C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 708 with ball-and-stick + neighbors within 5Å)
- `R708C_variant_card.md` — this card (source of truth)
- `R708C_variant_card.html` — styled printable card
- `R708C_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)
- `R708C_wildtype_interactions.pse` / `R708C_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.*