# WFS1 Wolframin — V415F Variant Card

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

*Valine → Phenylalanine at position 415 inside TM3. ClinVar Likely pathogenic, Cataract 41. AlphaMissense 0.574 (just above threshold), DynaMut2 ΔΔG -1.64 kcal/mol (destabilising) — close to Cat 2. Volume increase in TM3.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V415F (p.Valine415Phenylalanine) |
| **DNA change** | c.1243G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001702534 |
| **Amino acid change** | Valine (V) → Phenylalanine (F) — small branched hydrophobic replaced by aromatic hydrophobic. Volume increases substantially. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 415** | **93.25** — well-folded |
| **Domain** | TM3 (402-422), helical transmembrane |
| **Position context** | TM3 (residues 402–422) · position 415 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: 402-422 Helical
  - Natural variant: 415-415 in WFS1; greatly reduces protein expression compared to wild-type

> Position 415 sits in TM3. The AlphaFold model places V415 within 5 Å of ILE416 (2.5 Å), PHE414 (2.5 Å — already aromatic), SER418 (3.6 Å), VAL412 (3.6 Å), and SER353 (3.8 Å — TM2-TM3 cross-helix, same S353 as F350I Atlas card neighbor).

Replacing V415 with phenylalanine creates a tandem aromatic motif (F414-F415). The local TM3 packing is reorganized to accommodate the second aromatic ring. The TM2-TM3 cross-helix S353 contact (also touched by F350I) is perturbed.

The |ΔΔG| of 1.64 — close to the Cat 2 threshold — reflects substantial fold cost. AlphaMissense's 0.574 is borderline-pathogenic plus Cataract 41 clinical evidence confirms pathogenic consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5741** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.64 (Destabilising)** |
| Job ID | 177992009091 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992009091 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 2022/05/26 00:00 |
| Inheritance | Cataract 41 documented. |
| WFS1 variant landscape | V415F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41

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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 3/4 — Most Druggable (near Cat 2 boundary).</strong> |ΔΔG| = 1.64 — close to Cat 2. AlphaMissense 0.574 + Cataract 41 confirm pathogenic consequence.<br/><br/>Mechanism is volume mismatch in TM3 plus disruption of TM2-TM3 cross-helix contact (S353). Therapeutic strategy: TM2-TM3 interface site-directed design — same target as F350I.

**Why this card matters.** V415F + F350I both touch the S353/S418 TM2-TM3 interface — two variants converge on this previously-unidentified cross-helix target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V415F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 415 with ball-and-stick + neighbors within 5Å)
- `V415F_variant_card.md` — this card (source of truth)
- `V415F_variant_card.html` — styled printable card
- `V415F_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)
- `V415F_wildtype_interactions.pse` / `V415F_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.*