# WFS1 Wolframin — F413V Variant Card

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

*Phe→Val p413 TM3 AM=0.05 ddg=-0.42 pLDDT=92. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F413V (p.Phenylalanine413Valine) |
| **DNA change** | c.1237T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000166584 |
| **Amino acid change** | aromatic loss + volume reduction |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 413** | **91.69** — well-folded |
| **Domain** | TM3 (402-422), helical transmembrane |
| **Position context** | TM3 (402-422) |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 402-422 Helical

> Position analysis: VAL412 (2.5 Å — V412L/V412A!), PHE414 (2.5 Å — adjacent existing F, also TM3-TM10 contact partner of T641K!), LEU410 (3.8 Å). Multi-variant TM3 cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0549** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.42 (Destabilising)** |
| Job ID | 177992530286 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992530286 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/24 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | F413V 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 4 — Stable Fold, Function Disrupted**

<strong>Cat 3/4 — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

**Why this card matters.** TM3 cluster (V412L/A + F413V) — also F414 connects to TM10 T641K.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F413V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 413 with ball-and-stick + neighbors within 5Å)
- `F413V_variant_card.md` — this card (source of truth)
- `F413V_variant_card.html` — styled printable card
- `F413V_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)
- `F413V_wildtype_interactions.pse` / `F413V_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.*