# WFS1 Wolframin — R708L Variant Card

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

*Arginine → Leucine at position 708 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, auditory neuropathy. AlphaMissense 0.954, DynaMut2 ΔΔG +0.20 kcal/mol — STABILISING. A charge-loss variant where the fold tightens slightly.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R708L (p.Arginine708Leucine) |
| **DNA change** | c.2123G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002683858 |
| **Amino acid change** | Arginine (R) → Leucine (L) — large positively-charged guanidinium replaced by branched hydrophobic. Loss of charge entirely. |

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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 in the ER lumen (pLDDT 93). |
| **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 wolframin's C-terminal lumenal domain. The AlphaFold model places R708 within 5 Å of VAL709 (2.4 Å), VAL707 (2.5 Å — same V707 as V707F Atlas card), and GLU776 (3.8 Å — likely salt-bridge partner).

The wild-type arginine likely forms an intramolecular salt bridge with E776 across the lumenal fold. Replacing R708 with leucine eliminates that salt bridge entirely. The DynaMut2 ΔΔG of +0.20 (stabilising) reflects that the leucine packs more efficiently into the hydrophobic V707-V709 local environment than the long arginine side chain did.

AlphaMissense's 0.954 + auditory neuropathy clinical evidence confirm severe functional consequence. The mechanism is loss of the R708-E776 salt bridge that the wild-type fold relied on, even though the local packing improves.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9543** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.2 (Stabilising)** |
| Job ID | 177991929911 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991929911 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/12/22 00:00 |
| Inheritance | Auditory neuropathy documented. |
| WFS1 variant landscape | R708L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Auditory neuropathy

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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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.20 stabilising. AlphaMissense 0.954 + auditory neuropathy confirm severe functional consequence.<br/><br/>Mechanism is loss of R708-E776 salt bridge. Therapeutic strategy: bridge restoration through site-directed small molecules at the E776 microregion. Combined with V707F (adjacent position), drug discovery has convergent targets.

**Why this card matters.** R708L is another Atlas stabilising-but-pathogenic variant. Combined with V707F at the adjacent position, the 707-708 microregion has two convergent therapeutic targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R708L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 708 with ball-and-stick + neighbors within 5Å)
- `R708L_variant_card.md` — this card (source of truth)
- `R708L_variant_card.html` — styled printable card
- `R708L_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)
- `R708L_wildtype_interactions.pse` / `R708L_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.*