# WFS1 Wolframin — F350I Variant Card

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

*Phenylalanine → Isoleucine at position 350 inside TM2. ClinVar Likely pathogenic. AlphaMissense 0.934, DynaMut2 ΔΔG +0.52 kcal/mol — STABILISING. Aromatic-to-branched-aliphatic substitution in a TM helix.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F350I (p.Phenylalanine350Isoleucine) |
| **DNA change** | c.1048T>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003718608 |
| **Amino acid change** | Phenylalanine (F) → Isoleucine (I) — aromatic hydrophobic replaced by branched aliphatic hydrophobic. Aromatic π-system lost; volume comparable. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 350** | **93.38** — well-folded |
| **Domain** | TM2 (340-360), helical transmembrane |
| **Position context** | TM2 (residues 340–360) · position 350 mid-helix, bilayer-embedded (pLDDT 93 — high confidence). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 340-360 Helical
  - Natural variant: 350-350 in WFS1

> Position 350 sits in TM2. The AlphaFold model places F350 within 5 Å of ILE349 (2.5 Å), TYR351 (2.5 Å), SER418 (3.3 Å — TM2-TM3 cross-helix contact), SER353 (3.5 Å), and LEU347 (3.7 Å). The F350-S418 contact across helices is the structurally significant observation.

The wild-type phenylalanine's aromatic ring likely makes π-stacking or edge-face contact with Y351 and aromatic packing with the surrounding helices. Replacing it with isoleucine eliminates the aromatic character and replaces it with branched aliphatic packing. The DynaMut2 ΔΔG of +0.52 (stabilising) reflects that isoleucine packs efficiently into the local hydrophobic environment.

But AlphaMissense's 0.934 confirms severe functional consequence. The mechanism is loss of aromatic π-stacking with Y351 plus perturbation of the F350-S418 TM2-TM3 cross-helix contact.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9342** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.52 (Stabilising)** |
| Job ID | 177992005217 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992005217 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/07/28 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | F350I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.52 stabilising. AlphaMissense 0.934 confirms severe functional consequence.<br/><br/>Mechanism is loss of aromatic packing with Y351 plus TM2-TM3 interface disruption at S418. Therapeutic strategy: site-directed at the F350-Y351-S418 contact cluster.

**Why this card matters.** F350I joins the stabilising-but-pathogenic class. The TM2-TM3 cross-helix S418 contact identifies a previously-unseen TM-TM target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F350I_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 350 with ball-and-stick + neighbors within 5Å)
- `F350I_variant_card.md` — this card (source of truth)
- `F350I_variant_card.html` — styled printable card
- `F350I_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)
- `F350I_wildtype_interactions.pse` / `F350I_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.*