# WFS1 Wolframin — S430W Variant Card

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

*Serine → Tryptophan at position 430 inside TM4. ClinVar Likely pathogenic. AlphaMissense 0.979, DynaMut2 ΔΔG -0.74 kcal/mol (destabilising). A massive volume increase in a TM helix.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S430W (p.Serine430Tryptophan) |
| **DNA change** | c.1289C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001297548 |
| **Amino acid change** | Serine (S) → Tryptophan (W) — small polar hydroxyl replaced by bulky aromatic indole. Roughly four-fold side-chain volume increase plus aromatic π-system added. |

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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 the start of TM4 (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 430 sits near the start of TM4. The AlphaFold model places S430 within 5 Å of CYS429 (2.5 Å), GLU431 (2.5 Å — same E431 contacted by A559D and P428R), SER551 (4.0 Å — TM4-TM7 cross-helix), PRO428 (4.1 Å), and ALA433 (4.4 Å). The E431 contact at 2.5 Å is structurally significant — the wild-type serine's hydroxyl likely H-bonds to E431's carboxylate.

Replacing serine with tryptophan introduces a massive volume increase. The pocket sized for serine cannot accommodate tryptophan without substantial rearrangement. The H-bond to E431 is lost (tryptophan's indole is aromatic, not H-bond-donating in this geometry). The cross-helix contact to S551 in TM7 is perturbed.

The |ΔΔG| of 0.74 reflects fold absorption at meaningful cost. AlphaMissense's 0.979 confirms severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9793** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.74 (Destabilising)** |
| Job ID | 177991411668 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991411668 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 1/01/01 00:00 |
| Inheritance | Inheritance not specified. ClinVar Likely pathogenic. |
| WFS1 variant landscape | S430W is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for S430W)

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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| = 0.74 kcal/mol — fold survives. AlphaMissense 0.979 confirms severe functional consequence.<br/><br/>The mechanism is volume mismatch in TM4 plus loss of the S430-E431 H-bond. Therapeutic strategy: site-directed at the E431 microregion (also touched by A559D and P428R).

**Why this card matters.** S430W is the fourth Atlas variant contacting E431 (with A559D, P428R, E431Q in the next card). E431 emerges as a hub residue in the WFS1 lumenal-membrane interface — multiple pathogenic variants converge on it.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S430W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 430 with ball-and-stick + neighbors within 5Å)
- `S430W_variant_card.md` — this card (source of truth)
- `S430W_variant_card.html` — styled printable card
- `S430W_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)
- `S430W_wildtype_interactions.pse` / `S430W_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.*