# WFS1 Wolframin — S308C Variant Card

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

*Serine → Cysteine at position 308 in N-terminal cytoplasmic domain. ClinVar Conflicting including congenital bilateral perisylvian syndrome. AlphaMissense 0.642, ΔΔG -0.01 (neutral). pLDDT 61 borderline.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S308C (p.Serine308Cysteine) |
| **DNA change** | c.923C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001496445 |
| **Amino acid change** | Serine (S) → Cysteine (C) — small polar hydroxyl replaced by small thiol. Both small; chemistry shifts from OH to SH. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 308** | **61.47** — confident |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 308 (pLDDT 61 borderline). Near the TM1 boundary. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 308 near TM1 boundary. Neighbors: ARG309 (2.5 Å — same R309 as H313Y region), ALA307 (2.5 Å), ILE304 (3.8 Å), ASP305 (4.1 Å).

Replacing S308 with cysteine swaps hydroxyl for thiol. In the cytosol, the new C308 thiol is less reactive than in the ER lumen, but free cysteines in cytosol can still participate in glutathionylation or other regulatory thiol chemistry. ΔΔG essentially neutral; AM 0.642 + congenital syndrome confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6422** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.01 (Destabilising)** |
| Job ID | 177992466332 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992466332 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/07/27 00:00 |
| Inheritance | Congenital bilateral perisylvian syndrome documented. |
| WFS1 variant landscape | S308C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Congenital bilateral perisylvian syndrome

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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. AlphaMissense 0.642 + congenital syndrome confirm severe consequence.<br/><br/>Mechanism: hydroxyl-to-thiol substitution near R309. Therapeutic: site-directed at the cytoplasmic-TM1 boundary region.

**Why this card matters.** S308C joins the TM1-boundary cluster (with W314R, H313Y) and introduces a novel thiol regulatory chemistry consideration.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S308C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 308 with ball-and-stick + neighbors within 5Å)
- `S308C_variant_card.md` — this card (source of truth)
- `S308C_variant_card.html` — styled printable card
- `S308C_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)
- `S308C_wildtype_interactions.pse` / `S308C_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.*