# WFS1 Wolframin — S469L Variant Card

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

*Serine → Leucine at position 469 inside TM5. ClinVar Conflicting. AlphaMissense 0.18 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.14.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S469L (p.Serine469Leucine) |
| **DNA change** | c.1406C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001587484 |
| **Amino acid change** | Serine (S) → Leucine (L) — polar hydroxyl replaced by branched aliphatic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 469** | **71.19** — well-folded |
| **Domain** | TM5 (465-485), helical transmembrane |
| **Position context** | TM5 (residues 465–485) · position 469 (pLDDT 71). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 465-485 Helical

> Position 469 in TM5 — first TM5 variant at v3 depth. Neighbors: LEU468 (2.5 Å), LEU470 (2.5 Å), GLY466 (3.8 Å). Hydrophobic TM environment.

S469L removes hydroxyl from TM5 (favorable energetically), but the wild-type serine's H-bond capacity supported functional geometry. AM 0.18 under-call; Conflicting evidence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1761** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.14 (Destabilising)** |
| Job ID | 177992501609 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992501609 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/10/16 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | S469L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific 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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted (AM under-call).</strong> |ΔΔG| 0.14. AlphaMissense 0.18 below threshold. Limited clinical evidence.<br/><br/>Mechanism: lost serine H-bonding in TM5. Therapeutic: TM5 site-directed.

**Why this card matters.** S469L is the first TM5 variant in the Atlas at full v3 depth — establishes TM5 as a target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S469L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 469 with ball-and-stick + neighbors within 5Å)
- `S469L_variant_card.md` — this card (source of truth)
- `S469L_variant_card.html` — styled printable card
- `S469L_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)
- `S469L_wildtype_interactions.pse` / `S469L_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.*