# WFS1 Wolframin — M518K Variant Card

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

*Methionine → Lysine at position 518 in a connecting loop. ClinVar Conflicting including optic neuropathy. AlphaMissense 0.925, ΔΔG -0.64 (destabilising). Same position as M518I (Atlas card).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | M518K (p.Methionine518Lysine) |
| **DNA change** | c.1553T>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001320487 |
| **Amino acid change** | Methionine (M) → Lysine (K) — flexible sulfur-containing hydrophobic replaced by long positively-charged amine. Charge introduction into a hydrophobic loop position. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 518** | **84.12** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 518 (pLDDT 84). Same position as M518I. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 518 same neighbors as M518I: ALA519 (2.5 Å), ARG517 (2.5 Å — adjacent existing arginine), PHE515 (3.7 Å), LEU514 (3.8 Å), LEU521 (3.9 Å).

M518K is the second substitution at position 518. Unlike M518I (conservative hydrophobic-to-hydrophobic), M518K introduces a charged residue. The new K518 amine adjacent to existing R517 creates a two-basic cluster where wild-type had M518's sulfur chemistry.

The |ΔΔG| of 0.64 is larger than M518I's 0.29 — the charge introduction has greater structural cost than conservative volume change. AlphaMissense 0.925 + optic neuropathy confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9252** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.64 (Destabilising)** |
| Job ID | 177992301187 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992301187 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/08/01 00:00 |
| Inheritance | Optic neuropathy documented. |
| WFS1 variant landscape | M518K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Optic 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 3/4 — Most Druggable.</strong> |ΔΔG| = 0.64 — fold survives. AlphaMissense 0.925 + optic neuropathy confirm severe consequence.<br/><br/>Mechanism: charge introduction into the M518 hydrophobic environment, creating a two-basic cluster with R517. Therapeutic: same M518 microregion as M518I.

**Why this card matters.** M518K + M518I at same position — both pathogenic but through different mechanisms (charge introduction vs lost methionine chemistry).

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `M518K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 518 with ball-and-stick + neighbors within 5Å)
- `M518K_variant_card.md` — this card (source of truth)
- `M518K_variant_card.html` — styled printable card
- `M518K_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)
- `M518K_wildtype_interactions.pse` / `M518K_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.*