# WFS1 Wolframin — F329I Variant Card

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

*Phenylalanine → Isoleucine at position 329 inside TM1. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.22.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F329I (p.Phenylalanine329Isoleucine) |
| **DNA change** | c.985T>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000504708 |
| **Amino acid change** | Phenylalanine (F) → Isoleucine (I) — aromatic replaced by branched aliphatic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 329** | **77.00** — well-folded |
| **Domain** | TM1 (314-334), helical transmembrane |
| **Position context** | TM1 (residues 314–334) · position 329 near TM1 end (pLDDT 77). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 314-334 Helical

> Position 329 in TM1. Neighbors: ILE328 (2.5 Å), PHE330 (2.5 Å — F330-F331 cluster region; F331I!), ASN325 (3.6 Å — A325 in A326 region).

F329I loses aromatic. Adjacent to F331I (Atlas card). Both perturb the F329-F330-F331 aromatic cluster. AM 0.15 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1541** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.22 (Destabilising)** |
| Job ID | 177992502616 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992502616 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/03 00:00 |
| Inheritance | WFS1 spectrum + Wolfram. |
| WFS1 variant landscape | F329I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Wolfram syndrome 1

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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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.22. AlphaMissense 0.15 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: aromatic loss in F329-F330-F331 TM1 cluster. Therapeutic: TM1 multi-variant target.

**Why this card matters.** F329I + F331I — adjacent TM1 aromatic-loss variants in same F329-F330-F331 cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F329I_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 329 with ball-and-stick + neighbors within 5Å)
- `F329I_variant_card.md` — this card (source of truth)
- `F329I_variant_card.html` — styled printable card
- `F329I_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)
- `F329I_wildtype_interactions.pse` / `F329I_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.*