# WFS1 Wolframin — E680A Variant Card

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

*Glutamate → Alanine at position 680 in lumenal domain. ClinVar Conflicting including monogenic diabetes + Wolfram. AlphaMissense 0.34 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23 kcal/mol. Same position as E680Q — second substitution at 680.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E680A (p.Glutamate680Alanine) |
| **DNA change** | c.2039A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000286507 |
| **Amino acid change** | Glutamate (E) → Alanine (A) — small negatively-charged carboxylate replaced by small methyl-bearing hydrophobic. Charge lost + side chain reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 680** | **84.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 680 (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 680-680 in DFNA6; uncertain significance

> Position 680 same neighbors as E680Q: THR681 (2.5 Å), LYS679 (2.5 Å — wild-type salt-bridge partner), ALA677 (4.0 Å), ARG676 (4.1 Å — second nearby basic). E680A is more drastic than E680Q — eliminates the charge AND removes the side chain (compared to E680Q which kept H-bonding capacity through the amide).

The E680-K679 salt bridge is lost entirely. The R676 nearby basic loses its electrostatic counterpart through this position. AlphaMissense's 0.34 is below threshold (AM under-call); monogenic diabetes + Wolfram confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3424** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.23 (Destabilising)** |
| Job ID | 177992493528 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992493528 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/30 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | E680A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- 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| = 0.23. AlphaMissense 0.34 below threshold but monogenic diabetes + Wolfram confirm pathogenicity.<br/><br/>Mechanism: complete loss of E680-K679 salt bridge plus side-chain volume reduction. Therapeutic strategy: same K679 microregion as E680Q.

**Why this card matters.** E680A + E680Q at same position — both pathogenic at the K679 salt-bridge partner site.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E680A_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 680 with ball-and-stick + neighbors within 5Å)
- `E680A_variant_card.md` — this card (source of truth)
- `E680A_variant_card.html` — styled printable card
- `E680A_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)
- `E680A_wildtype_interactions.pse` / `E680A_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.*