# WFS1 Wolframin — K862N Variant Card

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

*Lysine → Asparagine at position 862 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.981, DynaMut2 ΔΔG -0.20 kcal/mol (mild destabilising). pLDDT 64 borderline. A charge-loss variant near the C-terminus.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K862N (p.Lysine862Asparagine) |
| **DNA change** | c.2586G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003338038 |
| **Amino acid change** | Lysine (K) → Asparagine (N) — large positively-charged primary amine replaced by neutral polar amide. Loss of charge and long side chain. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 862** | **64.12** — confident |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 862 near the C-terminus (pLDDT 64). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 862 sits near the C-terminus of wolframin's lumenal domain. The AlphaFold model places K862 within 5 Å of ILE863 (2.5 Å), VAL861 (2.5 Å), LYS843 (3.5 Å — second nearby lysine), ALA844 (4.0 Å), and GLU864 (4.6 Å — partner of E864K Atlas card).

The wild-type lysine likely forms a long-range salt bridge with E864 or contributes positive charge to a C-terminal surface patch including K843. Replacing K862 with N862 eliminates the positive charge and shortens the side chain. The mild |ΔΔG| of 0.20 reflects fold accommodation; AlphaMissense's 0.981 + Wolfram syndrome 1 clinical evidence confirm severe functional consequence.

Notably E864K (Atlas card adjacent) and K862N together establish the K862-E864 microregion as having multiple pathogenic variants — drug discovery here has convergent rescue opportunities.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9812** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.2 (Destabilising)** |
| Job ID | 177991931155 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991931155 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/08/20 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | K862N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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| = 0.20 — fold survives. AlphaMissense 0.981 + Wolfram 1 confirm severe functional consequence.<br/><br/>The mechanism is C-terminal surface charge loss. Therapeutic strategy: site-directed at the K862-E864 microregion — same target region as E864K.

**Why this card matters.** K862N + E864K together establish the C-terminal lumenal region as a multi-variant drug target. Two charge-flip-like variants in adjacent positions.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K862N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 862 with ball-and-stick + neighbors within 5Å)
- `K862N_variant_card.md` — this card (source of truth)
- `K862N_variant_card.html` — styled printable card
- `K862N_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)
- `K862N_wildtype_interactions.pse` / `K862N_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.*