# WFS1 Wolframin — Q687H Variant Card

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

*Glutamine → Histidine at position 687 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications. AlphaMissense 0.996 (near-maximum), DynaMut2 ΔΔG -0.19 kcal/mol (mild destabilising). Strong AM signal in the dense 684-688 cluster.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Q687H (p.Glutamine687Histidine) |
| **DNA change** | c.2061G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000427196 |
| **Amino acid change** | Glutamine (Q) → Histidine (H) — polar amide replaced by aromatic titratable basic residue. Aromatic character introduced; pH-dependent charge added. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 687** | **89.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 687 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 687 sits in the dense 684-688 cluster discussed in the A684T, A684V, R685P, I688F Atlas cards. The AlphaFold model places Q687 within 5 Å of THR686 (2.5 Å), ILE688 (2.5 Å — partner of I688F), LEU833 (3.6 Å — long-range), ALA684 (3.8 Å — partner of A684T, A684V), and MET683 (3.9 Å).

The wild-type glutamine's amide likely H-bonds with the surrounding polar residues in this cluster. Replacing Q687 with histidine introduces an aromatic imidazole with pH-dependent charge. The H-bond geometry changes substantially.

The |ΔΔG| of 0.19 reflects fold accommodation. AlphaMissense's 0.996 (near-maximum) is strong pathogenic signal. ClinVar conflicting classifications suggest context-dependent functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9955** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.19 (Destabilising)** |
| Job ID | 177992012581 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992012581 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/08/17 00:00 |
| Inheritance | Conflicting classifications. AD-leaning given DFNA6 association. |
| WFS1 variant landscape | Q687H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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| = 0.19 — fold survives. AlphaMissense 0.996 (near-maximum) confirms severe pathogenic mechanism.<br/><br/>Mechanism is amide-to-aromatic substitution disrupting the 684-688 cluster H-bond network. Therapeutic strategy: same cluster target as A684T, A684V, R685P, I688F.

**Why this card matters.** Q687H is the FIFTH Atlas variant in the 684-688 microregion. This is one of the densest multi-variant target clusters in the entire Atlas. Drug discovery here rescues five known pathogenic variants simultaneously.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Q687H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 687 with ball-and-stick + neighbors within 5Å)
- `Q687H_variant_card.md` — this card (source of truth)
- `Q687H_variant_card.html` — styled printable card
- `Q687H_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)
- `Q687H_wildtype_interactions.pse` / `Q687H_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.*