# WFS1 Wolframin — K363T Variant Card

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

*Lysine → Threonine at position 363 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.874, DynaMut2 ΔΔG -0.43 kcal/mol (destabilising). Charge-loss variant adjacent to T361 (T361I Atlas card).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K363T (p.Lysine363Threonine) |
| **DNA change** | c.1088A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001327580 |
| **Amino acid change** | Lysine (K) → Threonine (T) — large positively-charged amine replaced by small polar hydroxyl. Loss of charge and side-chain length. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 363** | **85.50** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 363 in a loop region adjacent to T361 (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 363 sits in a connecting loop, two residues from T361 (T361I Atlas card). The AlphaFold model places K363 within 5 Å of LEU362 (2.5 Å), VAL364 (2.5 Å), CYS360 (3.6 Å), ILE359 (3.8 Å), and GLN366 (4.2 Å).

The wild-type lysine at 363 is the partner residue identified in the T361I Atlas card — T361's hydroxyl was hypothesized to H-bond with K363's amine. K363T replaces lysine with threonine, which is precisely the residue that T361I introduced at the wild-type T position. The K363 amine is replaced by a hydroxyl.

This means K363T and T361I together replace the wild-type T361-K363 H-bond pair (hydroxyl-amine) with a T361-T363 pair (hydroxyl-hydroxyl in the T361 variant; or the wild-type T plus T363 in the K363T variant). The geometry changes but H-bonding may persist.

The |ΔΔG| of 0.43 reflects modest fold cost. AlphaMissense's 0.874 + Wolfram 1 confirm severe functional consequence — the partner-recognition geometry depends on the precise wild-type chemistry, not just the H-bonding capacity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8740** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.43 (Destabilising)** |
| Job ID | 177992006744 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992006744 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 2021/11/25 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | K363T 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| = 0.43 — fold survives. AlphaMissense 0.874 + Wolfram 1 confirm severe functional consequence.<br/><br/>Mechanism is disruption of the T361-K363 H-bond pair. Therapeutic strategy: same microregion as T361I.

**Why this card matters.** K363T and T361I are sister variants at the same H-bond partner pair. Drug discovery in the T361-K363 microregion has two convergent variant targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K363T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 363 with ball-and-stick + neighbors within 5Å)
- `K363T_variant_card.md` — this card (source of truth)
- `K363T_variant_card.html` — styled printable card
- `K363T_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)
- `K363T_wildtype_interactions.pse` / `K363T_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.*