# WFS1 Wolframin — K705E Variant Card

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

*Lysine → Glutamate at position 705 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Cataract 41. AlphaMissense 0.975, DynaMut2 ΔΔG -0.17 kcal/mol (mild destabilising). Charge-flip variant at the SAME position as K705N (Atlas card adjacent).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K705E (p.Lysine705Glutamate) |
| **DNA change** | c.2113A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001685475 |
| **Amino acid change** | Lysine (K) → Glutamate (E) — large positively-charged amine replaced by small negatively-charged carboxylate. Complete charge sign reversal. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 705** | **90.00** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 705 in the ER lumen (pLDDT 90). Same position as K705N. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 705 same neighbor environment as K705N: TYR706 (2.4 Å), PHE704 (2.5 Å), THR778 (3.6 Å), GLN819 (4.4 Å), ARG703 (4.5 Å).

K705E is the charge-flip variant complementing K705N (charge-neutral) at this position. Where the wild-type K705 made a long-range contact (likely cation-π or salt bridge) with residues across the fold, the variant E705 makes opposite-sign electrostatic contacts. The R703 neighbor at 4.5 Å — previously experiencing K705's same-sign positive charge — now experiences an opposite-sign attractive contact.

The |ΔΔG| of 0.17 is mild — fold accommodates the charge flip easily. AlphaMissense's 0.975 + Cataract 41 clinical evidence confirm severe functional consequence. The mechanism is charge-reversal at the long-range contact position that K705 supplied positive charge to.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9750** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.17 (Destabilising)** |
| Job ID | 177992299337 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992299337 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/02/26 00:00 |
| Inheritance | Cataract 41 documented. |
| WFS1 variant landscape | K705E is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41

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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| = 0.17 — fold survives. AlphaMissense 0.975 + Cataract 41 confirm severe functional consequence.<br/><br/>Mechanism is charge-flip at K705 disrupting long-range contacts (THR778, GLN819). Therapeutic strategy: same microregion as K705N.

**Why this card matters.** K705E + K705N at the same position with different chemistry — both pathogenic. The K705 position is structurally critical regardless of which residue substitutes.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K705E_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 705 with ball-and-stick + neighbors within 5Å)
- `K705E_variant_card.md` — this card (source of truth)
- `K705E_variant_card.html` — styled printable card
- `K705E_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)
- `K705E_wildtype_interactions.pse` / `K705E_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.*