# WFS1 Wolframin — T337I Variant Card

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

*Threonine → Isoleucine at position 337 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.865, DynaMut2 ΔΔG -0.48 kcal/mol (destabilising). pLDDT 65 borderline.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | T337I (p.Threonine337Isoleucine) |
| **DNA change** | c.1010C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002203515 |
| **Amino acid change** | Threonine (T) → Isoleucine (I) — small polar hydroxyl replaced by branched aliphatic hydrophobic. Loss of H-bonding. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 337** | **65.12** — confident |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 337 in a borderline-confidence region (pLDDT 65). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 337 sits in a connecting loop near TM2. The AlphaFold model places T337 within 5 Å of ILE338 (2.4 Å), LEU336 (2.5 Å), ASN335 (4.1 Å), ASP339 (4.2 Å), and PHE340 (4.4 Å). The local environment is mixed polar-hydrophobic.

The wild-type threonine's hydroxyl likely H-bonds with the nearby N335 or D339. Replacing it with isoleucine eliminates the H-bonding capacity. The fold absorbs the substitution (|ΔΔG| 0.48), but the local H-bond network reorganizes.

AlphaMissense 0.865 + Wolfram 1 confirm pathogenic consequence. The mechanism is loss of T337's H-bonding role in the loop's polar network. pLDDT 65 is borderline; structural details deserve wet-lab confirmation.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8645** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.48 (Destabilising)** |
| Job ID | 177992006426 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992006426 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/08/26 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | T337I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

---

## 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 (pLDDT caveat).</strong> |ΔΔG| = 0.48 — fold survives. AlphaMissense 0.865 + Wolfram 1 confirm pathogenic consequence. pLDDT 65 borderline.<br/><br/>Mechanism is loss of T337 H-bonding role. Therapeutic strategy: site-directed at the connecting loop polar network.

**Why this card matters.** T337I is another threonine-to-isoleucine variant in the Atlas (with T361I). The class of T→I substitutions, removing H-bonding capacity, recurs at multiple positions and is consistently pathogenic.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `T337I_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 337 with ball-and-stick + neighbors within 5Å)
- `T337I_variant_card.md` — this card (source of truth)
- `T337I_variant_card.html` — styled printable card
- `T337I_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)
- `T337I_wildtype_interactions.pse` / `T337I_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*