# WFS1 Wolframin — A342T Variant Card

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

*Alanine → Threonine at position 342 inside TM2. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.72.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | A342T (p.Alanine342Threonine) |
| **DNA change** | c.1024G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000130747 |
| **Amino acid change** | Alanine (A) → Threonine (T) — small replaced by polar hydroxyl. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 342** | **73.12** — well-folded |
| **Domain** | TM2 (340-360), helical transmembrane |
| **Position context** | TM2 (residues 340–360) · position 342 near TM2 start (pLDDT 73). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 340-360 Helical

> Position 342 at TM2 start. Neighbors: PHE343 (2.4 Å), PHE341 (2.5 Å — aromatic cluster start), TRP867 (3.6 Å — long-range to TM11 W867!). The W867 contact is structurally significant — TM2-TM11 cross-helix contact.

A342T introduces polarity into TM2 + perturbs TM2-TM11 cross-helix W867 contact. AM 0.13 under-call; multi-phenotype confirms.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1312** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.72 (Destabilising)** |
| Job ID | 177992505905 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992505905 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/08/28 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | A342T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.72. AlphaMissense 0.13 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: polarity in TM2 + TM2-TM11 W867 cross-helix disruption. Therapeutic: TM2-TM11 interface.

**Why this card matters.** A342T identifies a TM2-TM11 cross-helix contact at W867 — new interface target.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A342T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 342 with ball-and-stick + neighbors within 5Å)
- `A342T_variant_card.md` — this card (source of truth)
- `A342T_variant_card.html` — styled printable card
- `A342T_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)
- `A342T_wildtype_interactions.pse` / `A342T_mutant_interactions.pse` — PyMOL sessions

---

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