# WFS1 Wolframin — I688F Variant Card

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

*Isoleucine → Phenylalanine at position 688 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.406 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.64 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | I688F (p.Isoleucine688Phenylalanine) |
| **DNA change** | c.2062A>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003393279 |
| **Amino acid change** | Isoleucine (I) → Phenylalanine (F) — branched aliphatic hydrophobic replaced by aromatic hydrophobic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 688** | **89.31** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 688 in the ER lumen (pLDDT 89). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 688 sits adjacent to several R558 microregion-related residues. The AlphaFold model places I688 within 5 Å of LEU689 (2.5 Å), GLN687 (2.5 Å — partner of Q687H Atlas card), ARG685 (3.8 Å — partner of R685P), SER691 (3.9 Å), and ALA684 (4.0 Å — partner of A684T and A684V).

Replacing I688 with phenylalanine adds aromatic volume to a tightly-packed region containing R685, A684, Q687 — all known pathogenic variant positions. The F688 introduction reorganizes the local packing.

The |ΔΔG| of 0.64 reflects fold accommodation. AlphaMissense's 0.406 is below threshold — AM under-call. ClinVar Pathogenic + Wolfram 1 establishes clinical relevance.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4058** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.64 (Destabilising)** |
| Job ID | 177992010112 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992010112 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/12/19 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | I688F 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| = 0.64 — fold survives. AlphaMissense 0.406 below threshold but ClinVar Pathogenic + Wolfram 1.<br/><br/>Mechanism is volume mismatch in the R685-A684-Q687 multi-variant microregion. Therapeutic strategy: same target cluster as A684T, A684V, R685P, Q687H.

**Why this card matters.** I688F joins the dense 684-688 multi-variant cluster — six Atlas variants (A684T, A684V, R685P, Q687H, I688F, plus broader region) converge here.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `I688F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 688 with ball-and-stick + neighbors within 5Å)
- `I688F_variant_card.md` — this card (source of truth)
- `I688F_variant_card.html` — styled printable card
- `I688F_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)
- `I688F_wildtype_interactions.pse` / `I688F_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.*