# WFS1 Wolframin — F783L Variant Card

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

*Phenylalanine → Leucine at position 783 in lumenal domain. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.414 (below threshold), ΔΔG -0.22. pLDDT 61 borderline.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F783L (p.Phenylalanine783Leucine) |
| **DNA change** | c.2347T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215370 |
| **Amino acid change** | Phenylalanine (F) → Leucine (L) — aromatic replaced by branched aliphatic. Aromatic loss. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 783** | **60.84** — confident |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 783 (pLDDT 61 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 783 in lumenal domain. Neighbors: PRO782 (2.5 Å — partner of G702S neighbor P782), SER784 (2.5 Å), GLN667 (4.4 Å — long-range to Y669 cluster), SER785 (4.7 Å).

F783L removes aromatic. Q667 long-range contact suggests F783 mediates packing between this site and the Y669-C673 cluster. AM 0.414 under-call; WFS1 spectrum confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4139** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.22 (Destabilising)** |
| Job ID | 177992473308 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992473308 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/07/31 00:00 |
| Inheritance | WFS1 spectrum. |
| WFS1 variant landscape | F783L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Inborn genetic diseases

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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, pLDDT borderline).</strong> |ΔΔG| 0.22. AlphaMissense 0.414 below threshold.<br/><br/>Mechanism: lost aromatic + perturbation of long-range Q667 contact. Therapeutic: 783-667 cross-domain.

**Why this card matters.** F783L identifies a long-range contact to the Y669-Q667 cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F783L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 783 with ball-and-stick + neighbors within 5Å)
- `F783L_variant_card.md` — this card (source of truth)
- `F783L_variant_card.html` — styled printable card
- `F783L_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)
- `F783L_wildtype_interactions.pse` / `F783L_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.*