# WFS1 Wolframin — T361S Variant Card

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

*Threonine → Serine at position 361 in a connecting loop. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.756, ΔΔG +0.03 (neutral). Same position as T361I (Atlas flagship pathogenic-stabilising card).*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | T361S (p.Threonine361Serine) |
| **DNA change** | c.1082C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001486730 |
| **Amino acid change** | Threonine (T) → Serine (S) — small polar hydroxyl with methyl replaced by small polar hydroxyl without methyl. Conservative. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 361** | **91.12** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 361 (pLDDT 91). Same as T361I. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 361 same neighbors as T361I: LEU362 (2.5 Å), CYS360 (2.5 Å), VAL358 (3.8 Å), MET357 (3.9 Å).

T361S is the most conservative substitution possible at position 361 — preserving the H-bonding hydroxyl while only removing the methyl group. ΔΔG essentially neutral. Yet AlphaMissense 0.756 + Wolfram + Wolfram-like confirm pathogenicity.

Mechanism is the same as T361I (Atlas card): functional disruption rather than fold disruption. The K363 H-bond partner geometry is fine-tuned by the wild-type threonine's specific methyl positioning that serine cannot replicate.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7559** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.03 (Stabilising)** |
| Job ID | 177992464874 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992464874 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/10/25 00:00 |
| Inheritance | AD and AR documented. |
| WFS1 variant landscape | T361S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome
- 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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG ≈ 0. AlphaMissense 0.756 + multi-syndrome confirm severe consequence.<br/><br/>Mechanism: fine-grained geometry disruption at the T361-K363 H-bond pair. Therapeutic: same target as T361I.

**Why this card matters.** T361S + T361I at same position — both pathogenic by functional mechanism. Position 361 demonstrates that even the most conservative T→S substitution breaks function.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `T361S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 361 with ball-and-stick + neighbors within 5Å)
- `T361S_variant_card.md` — this card (source of truth)
- `T361S_variant_card.html` — styled printable card
- `T361S_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)
- `T361S_wildtype_interactions.pse` / `T361S_mutant_interactions.pse` — PyMOL sessions

---

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