# WFS1 Wolframin — L842F Variant Card

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

*Leucine → Phenylalanine at position 842 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.956, DynaMut2 ΔΔG -0.61 kcal/mol (destabilising). Volume increase variant near the L829 region.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L842F (p.Leucine842Phenylalanine) |
| **DNA change** | c.2524C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001518006 |
| **Amino acid change** | Leucine (L) → Phenylalanine (F) — branched aliphatic hydrophobic replaced by aromatic hydrophobic. Volume increase, aromatic π-system added. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 842** | **88.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 842 in the ER lumen (pLDDT 89). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 842 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L842 within 5 Å of GLU841 (2.5 Å), LYS843 (2.5 Å — same K843 as the K862-K843 cluster), ARG805 (3.7 Å — long-range, near A806P), SER826 (4.2 Å), and ALA844 (4.7 Å).

The wild-type leucine fits cleanly into this mixed polar-basic environment. Replacing it with phenylalanine adds aromatic volume that the local pocket was not sized for. The K843 + L842 + R805 region is reorganized.

The |ΔΔG| of 0.61 reflects modest fold cost. AlphaMissense's 0.956 confirms severe functional consequence. The proximity to A806P (3.7 Å through R805) and the K843 contact suggest this region is a multi-variant hub.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9560** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.61 (Destabilising)** |
| Job ID | 177991929366 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991929366 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/03/23 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | L842F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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| = 0.61 — fold survives. AlphaMissense 0.956 confirms severe functional consequence.<br/><br/>Mechanism is volume mismatch in the E841-L842-K843-R805 polar-basic environment. Therapeutic strategy: site-directed at this microregion.

**Why this card matters.** L842F joins A806P and the K843/K862 cluster as part of a multi-variant lumenal C-terminal target region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L842F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 842 with ball-and-stick + neighbors within 5Å)
- `L842F_variant_card.md` — this card (source of truth)
- `L842F_variant_card.html` — styled printable card
- `L842F_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)
- `L842F_wildtype_interactions.pse` / `L842F_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.*