# WFS1 Wolframin — E158K Variant Card

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

*Glutamate → Lysine at position 158 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1 + Cataract 41. AlphaMissense 0.378 (below threshold), ΔΔG +0.55 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E158K (p.Glutamate158Lysine) |
| **DNA change** | c.472G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001404588 |
| **Amino acid change** | Glutamate (E) → Lysine (K) — charge reversal. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 158** | **86.62** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 158 (pLDDT 87). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 158 in cytoplasmic domain. Neighbors: ASN159 (2.5 Å), SER157 (2.5 Å), THR156 (4.0 Å), GLU160 (4.6 Å — second nearby glutamate).

E158K reverses charge. The E158-E160 charged pair becomes K158-E160 alternating charges. Fold stabilises slightly. AM 0.378 under-call; Wolfram + Cataract confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3776** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.55 (Stabilising)** |
| Job ID | 177992477506 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992477506 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/05/02 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | E158K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted (AM under-call, stabilising).</strong> ΔΔG +0.55. AlphaMissense 0.378 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: charge-flip in E158-E160 pair. Therapeutic: cytoplasmic recognition surface.

**Why this card matters.** E158K joins charge-flip class + AM-under-call class. Cytoplasmic recognition-surface disruption.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E158K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 158 with ball-and-stick + neighbors within 5Å)
- `E158K_variant_card.md` — this card (source of truth)
- `E158K_variant_card.html` — styled printable card
- `E158K_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)
- `E158K_wildtype_interactions.pse` / `E158K_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.*