# WFS1 Wolframin — V707F Variant Card

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

*Valine → Phenylalanine at position 707 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic for classical autosomal recessive Wolfram syndrome 1. AlphaMissense 0.935, DynaMut2 ΔΔG -0.31 kcal/mol (destabilising). A conservative-to-aromatic substitution in a critical lumenal position.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V707F (p.Valine707Phenylalanine) |
| **DNA change** | c.2119G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000030552 |
| **Amino acid change** | Valine (V) → Phenylalanine (F) — a small branched hydrophobic replaced by a large aromatic. Volume increases substantially; π-electron system added where wild-type had only aliphatic carbons. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 707** | **92.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 707 in the ER lumen with high AlphaFold confidence (pLDDT 92). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 707 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places V707 within 5 Å of ARG708 (2.4 Å), TYR706 (2.5 Å), GLU776 (3.5 Å — long-range contact), PHE704 (4.2 Å — another long-range), and ILE777 (4.5 Å). The local environment combines basic (R708), aromatic (Y706, F704), and acidic (E776) residues.

The wild-type valine at 707 provides moderate hydrophobic packing into this mixed-character pocket. The branched aliphatic side chain fits cleanly between the surrounding residues without crowding.

Replacing valine with phenylalanine introduces a substantial volume increase plus an aromatic ring system. The local pocket — sized for valine — must rearrange to accommodate the larger phenyl ring. The two nearby aromatics (Y706 at 2.5 Å, F704 at 4.2 Å) could engage in π-stacking with the new F707, creating a three-aromatic cluster that the wild-type fold did not have. Whether this rearrangement is productive (stable three-aromatic stack) or destructive (disrupting Y706/F704 contacts with their own partners) depends on the specific geometry the variant fold adopts.

The |ΔΔG| of 0.31 indicates the fold absorbs the substitution. AlphaMissense's 0.935 score reflects the functional consequence — the rearranged aromatic cluster disrupts whatever interaction the wild-type valine geometry enabled.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9354** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.31 (Destabilising)** |
| Job ID | 177990263996 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990263996 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 2008/12/15 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented in ClinVar. |
| WFS1 variant landscape | V707F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.31 kcal/mol — fold survives. AlphaMissense 0.935 confirms severe functional consequence.<br/><br/>The mechanism is local volume mismatch creating an aromatic cluster (F707 + Y706 + F704) where the wild-type valine maintained a smaller hydrophobic pocket. Therapeutic strategy: site-directed small molecules that compensate for the disrupted Y706/F704 geometry by occupying the wild-type V707 niche.

**Why this card matters.** V707F demonstrates that classical Wolfram syndrome 1 (AR inheritance) is well-represented in the Atlas's most-druggable category. The mechanism — local volume disruption in a lumenal pocket — is straightforward and amenable to structure-based design.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V707F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 707 with ball-and-stick + neighbors within 5Å)
- `V707F_variant_card.md` — this card (source of truth)
- `V707F_variant_card.html` — styled printable card
- `V707F_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)
- `V707F_wildtype_interactions.pse` / `V707F_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.*