# WFS1 Wolframin — P533S Variant Card

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

*Proline → Serine at position 533 inside TM7. ClinVar Conflicting classifications including optic atrophy and DFNA6. AlphaMissense 0.979, DynaMut2 ΔΔG -1.33 kcal/mol (destabilising). Proline-removal in TM7 with substantial structural cost.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P533S (p.Proline533Serine) |
| **DNA change** | c.1597C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000137914 |
| **Amino acid change** | Proline (P) → Serine (S) — rigid helix-breaking residue replaced by small polar hydroxyl. Removes backbone constraint; adds H-bond capacity. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 533** | **84.00** — well-folded |
| **Domain** | TM7 (529-549), helical transmembrane |
| **Position context** | TM7 (residues 529–549) · position 533 near the start of TM7 (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 529-549 Helical

> Position 533 sits in TM7 near its start. The AlphaFold model places P533 within 5 Å of TYR534 (2.5 Å), VAL532 (2.5 Å), TYR405 (4.0 Å — TM3-TM7 cross-helix!), TYR530 (4.2 Å), and LEU535 (4.4 Å). The TYR405 contact at 4.0 Å is structurally significant — a TM3-TM7 helix-helix interaction through this proline position.

The wild-type proline at 533 defines TM7's helix-initiation geometry. Removing it eliminates that controlled kink, freeing the backbone. The introduced serine adds a polar hydroxyl into the bilayer-embedded environment, slightly unfavorable.

The |ΔΔG| of 1.33 reflects meaningful fold cost. The TM3-TM7 cross-helix contact at TYR405 is perturbed. AlphaMissense's 0.979 + WFS1-Related Spectrum Disorders + optic atrophy + DFNA6 clinical evidence confirm severe functional consequence across multiple tissue contexts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9786** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.33 (Destabilising)** |
| Job ID | 177992014107 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992014107 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/03/01 00:00 |
| Inheritance | Both AD (DFNA6) and AR documented. |
| WFS1 variant landscape | P533S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Optic atrophy
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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| = 1.33 — fold survives at meaningful cost. AlphaMissense 0.979 + three documented phenotypes confirm severe functional consequence.<br/><br/>Mechanism is loss of TM7 helix-initiation geometry plus disruption of TM3-TM7 cross-helix contact at TYR405. Therapeutic strategy: TM3-TM7 interface site-directed.

**Why this card matters.** P533S identifies a previously-unseen TM3-TM7 interface at the TYR405 contact (4.0 Å). The Atlas surfaces this as a new cross-helix therapeutic target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P533S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 533 with ball-and-stick + neighbors within 5Å)
- `P533S_variant_card.md` — this card (source of truth)
- `P533S_variant_card.html` — styled printable card
- `P533S_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)
- `P533S_wildtype_interactions.pse` / `P533S_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.*