# WFS1 Wolframin — S430L Variant Card

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

*Serine → Leucine at position 430 inside TM4. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.932, ΔΔG -0.01 (neutral). Same position as S430W (Atlas card adjacent).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S430L (p.Serine430Leucine) |
| **DNA change** | c.1289C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001484968 |
| **Amino acid change** | Serine (S) → Leucine (L) — small polar hydroxyl replaced by branched aliphatic hydrophobic. Loss of H-bond capacity; modest volume increase. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 430** | **89.75** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | TM4 (residues 427–447) · position 430 near TM4 start (pLDDT 90). Same position as S430W. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical

> Position 430 sits in TM4 with the E431 hub contact. Same neighbors as S430W: CYS429 (2.5 Å), GLU431 (2.5 Å — E431 hub), SER551 (4.0 Å — TM4-TM7 cross-helix), PRO428 (4.1 Å), ALA433 (4.4 Å).

S430L is the second substitution at position 430 (with S430W). Where S430W introduced massive aromatic volume, S430L introduces conservative aliphatic volume. The H-bond between S430's hydroxyl and E431's carboxylate is lost in both — same mechanism.

The near-zero ΔΔG indicates fold easily accommodates the more conservative leucine. AlphaMissense 0.932 + Wolfram 1 confirm severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9325** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.01 (Destabilising)** |
| Job ID | 177992300983 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992300983 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/07/24 00:00 |
| Inheritance | Wolfram syndrome 1 documented (conflicting classifications). |
| WFS1 variant landscape | S430L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 — fold unchanged. AlphaMissense 0.932 confirms severe functional consequence.<br/><br/>Mechanism: loss of S430-E431 H-bond. Therapeutic: same E431 hub target as S430W.

**Why this card matters.** S430L + S430W at same position — both pathogenic, both targeting E431 hub. Drug discovery at E431 has now 6+ convergent variant targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S430L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 430 with ball-and-stick + neighbors within 5Å)
- `S430L_variant_card.md` — this card (source of truth)
- `S430L_variant_card.html` — styled printable card
- `S430L_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)
- `S430L_wildtype_interactions.pse` / `S430L_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.*