# WFS1 Wolframin — F775V Variant Card

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

*Phenylalanine → Valine at position 775. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.941, ΔΔG -1.57 (substantial destabilization). Aromatic loss in a cross-domain contact position.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F775V (p.Phenylalanine775Valine) |
| **DNA change** | c.2323T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000166605 |
| **Amino acid change** | Phenylalanine (F) → Valine (V) — aromatic hydrophobic replaced by branched aliphatic. Aromatic π-system lost; volume reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 775** | **93.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 775 (pLDDT 94 — high confidence). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 775 sits in the lumenal domain. Neighbors: GLU776 (2.4 Å — partner of R708 salt-bridge), LYS774 (2.5 Å), ARG708 (3.3 Å — direct R708 contact!), ALA806 (3.7 Å — partner of A806P).

The wild-type phenylalanine at 775 likely participates in the R708-E776 salt-bridge geometry through cation-π interaction between F775's ring and R708's guanidinium. Replacing F775 with valine eliminates this cation-π contribution and reduces the aromatic packing supporting the R708-E776 salt bridge.

The |ΔΔG| of 1.57 reflects substantial fold cost. AlphaMissense 0.941 + Wolfram 1 confirm severe consequence. F775V joins R708L, R708C, A806P as multi-variant convergence on the 775-806 microregion.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9405** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.57 (Destabilising)** |
| Job ID | 177992300526 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992300526 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/03/23 00:00 |
| Inheritance | Wolfram syndrome 1 documented. |
| WFS1 variant landscape | F775V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Inborn genetic diseases

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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.</strong> |ΔΔG| = 1.57 — fold survives at meaningful cost. AlphaMissense 0.941 + Wolfram 1 confirm severe consequence.<br/><br/>Mechanism: loss of F775 cation-π contribution to R708-E776 salt-bridge geometry. Therapeutic: same R708-E776-F775 microregion (multi-variant target).

**Why this card matters.** F775V is the fourth variant in the 707-708-775-806 microregion (with V707F, R708L, R708C, A806P). Drug discovery here has multi-variant convergence.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F775V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 775 with ball-and-stick + neighbors within 5Å)
- `F775V_variant_card.md` — this card (source of truth)
- `F775V_variant_card.html` — styled printable card
- `F775V_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)
- `F775V_wildtype_interactions.pse` / `F775V_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.*