# WFS1 Wolframin — C541W Variant Card

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

*Cysteine → Tryptophan at position 541 inside TM7. ClinVar Conflicting including Wolfram. AlphaMissense 0.657, ΔΔG -1.54.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | C541W (p.Cysteine541Tryptophan) |
| **DNA change** | c.1623T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001046024 |
| **Amino acid change** | Cysteine (C) → Tryptophan (W) — small thiol replaced by bulky aromatic indole. Massive volume increase + loss of disulfide potential. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 541** | **90.12** — well-folded |
| **Domain** | TM7 (529-549), helical transmembrane |
| **Position context** | TM7 (residues 529–549) · position 541 (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 529-549 Helical

> Position 541 in TM7 (same broader region as L543P, L543F). Neighbors: TRP540 (2.5 Å — adjacent existing tryptophan!), GLU542 (2.5 Å), THR440 (3.4 Å — TM4-TM7 cross-helix!), PHE538 (3.5 Å).

The wild-type C541 is a small thiol in a bilayer-embedded position with aromatic neighbor (W540) and TM4 cross-contact (T440). Replacing it with tryptophan adds massive aromatic volume — creating W540-W541 tandem tryptophan motif. |ΔΔG| 1.54 substantial. AM 0.657 + Wolfram confirm severe consequence.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6570** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.54 (Destabilising)** |
| Job ID | 177992465814 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992465814 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/05/23 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | C541W is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Inborn genetic diseases

---

## 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| = 1.54. AlphaMissense 0.657 + Wolfram confirm severe consequence.<br/><br/>Mechanism: tandem tryptophan motif creation + TM4-TM7 cross-helix disruption at T440. Therapeutic: TM4-TM7 interface site-directed.

**Why this card matters.** C541W identifies a TM4-TM7 cross-helix contact at T440 — adding to the F408 (TM3-TM7) and S444/S551 (TM4-TM7) cross-helix targets.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `C541W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 541 with ball-and-stick + neighbors within 5Å)
- `C541W_variant_card.md` — this card (source of truth)
- `C541W_variant_card.html` — styled printable card
- `C541W_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)
- `C541W_wildtype_interactions.pse` / `C541W_mutant_interactions.pse` — PyMOL sessions

---

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