# WFS1 Wolframin — E717K Variant Card

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

*Glutamate → Lysine at position 717 in lumenal domain. ClinVar Conflicting with broad clinical spectrum — Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome. AlphaMissense 0.36 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.18 kcal/mol (mild destabilising). Charge-flip adjacent to the N714 polar network.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E717K (p.Glutamate717Lysine) |
| **DNA change** | c.2149G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000449390 |
| **Amino acid change** | Glutamate (E) → Lysine (K) — negatively-charged carboxylate replaced by positively-charged primary amine. Complete charge sign reversal. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 717** | **85.62** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 717 in the ER lumen (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 717 sits in wolframin's C-terminal lumenal domain. Neighbors: SER718 (2.5 Å), ALA716 (2.5 Å — adjacent to N714 cluster), ASN714 (3.8 Å — the N714T/N714S/N714K position!). The N714 contact at 3.8 Å places E717 in direct structural proximity to the densest multi-variant target in the Atlas (the D713-N714-D771-K768 polar network).

The wild-type E717 likely contributes negative charge to the polar network surrounding N714. Replacing E717 with lysine reverses the charge sign — the network now has K717 + the existing K768 plus N714's amide where the wild-type had E717 + N714.

The |ΔΔG| of 0.18 is mild. AlphaMissense's 0.36 is below threshold (AM under-call). The broad clinical spectrum (three phenotypes: Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome) plus the structural mechanism confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3610** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.18 (Destabilising)** |
| Job ID | 177992479188 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992479188 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/12/10 00:00 |
| Inheritance | Multi-phenotype AD and AR. |
| WFS1 variant landscape | E717K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Wolfram syndrome 1
- Wolfram-like syndrome

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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| = 0.18. AlphaMissense 0.36 below threshold but THREE documented phenotypes confirm severe consequence.<br/><br/>Mechanism: charge-flip immediately adjacent to the N714 polar network. Therapeutic strategy: same D713-N714-D771-K768 microregion as N714T/S/K, D771H, D771Y.

**Why this card matters.** E717K is the SIXTH Atlas variant directly involving the D713-N714-D771-K768 polar network — confirming this region as one of the densest multi-variant therapeutic targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E717K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 717 with ball-and-stick + neighbors within 5Å)
- `E717K_variant_card.md` — this card (source of truth)
- `E717K_variant_card.html` — styled printable card
- `E717K_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)
- `E717K_wildtype_interactions.pse` / `E717K_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.*