# WFS1 Wolframin — L499F Variant Card

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

*Leucine → Phenylalanine at position 499 inside TM6. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.11 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.62.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L499F (p.Leucine499Phenylalanine) |
| **DNA change** | c.1495C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045436 |
| **Amino acid change** | Leucine (L) → Phenylalanine (F) — branched aliphatic to aromatic. Volume increase + aromatic introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 499** | **80.62** — well-folded |
| **Domain** | TM6 (496-516), helical transmembrane |
| **Position context** | TM6 (residues 496–516) · position 499 near TM6 start (pLDDT 81). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 496-516 Helical

> Position 499 in TM6 near start. Neighbors: ASN500 (2.4 Å), VAL498 (2.5 Å), VAL491 (3.6 Å). Conservative aliphatic environment.

L499F introduces aromatic volume in TM6. AM 0.11 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1057** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.62 (Destabilising)** |
| Job ID | 177992509282 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992509282 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/27 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | L499F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Monogenic diabetes

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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 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.62. AlphaMissense 0.11 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: volume increase in TM6 start. Therapeutic: TM6 cluster (with P504L, C505Y, Y508C, V503G).

**Why this card matters.** L499F extends TM6 multi-variant cluster — six variants now converge on TM6 mid-helix region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L499F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 499 with ball-and-stick + neighbors within 5Å)
- `L499F_variant_card.md` — this card (source of truth)
- `L499F_variant_card.html` — styled printable card
- `L499F_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)
- `L499F_wildtype_interactions.pse` / `L499F_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.*