# WFS1 Wolframin — R456H Variant Card

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

*Arginine → Histidine at position 456 in connecting loop. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.16 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.26 (substantial). Adjacent to R457S.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R456H (p.Arginine456Histidine) |
| **DNA change** | c.1367G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045434 |
| **Amino acid change** | Arginine (R) → Histidine (H) — charge partial-reduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 456** | **85.69** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 456 (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Natural variant: 456-456 in dbSNP:rs1801208

> Position 456 in connecting loop. Neighbors: ARG457 (2.5 Å — R457S partner!), THR455 (2.5 Å), GLU452 (3.6 Å — likely salt-bridge).

R456H + R457S both at the R456-R457 double-arginine cluster. Partial charge reduction + perturbed E452 salt bridge. |ΔΔG| 1.26 substantial; AM 0.16 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1585** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.26 (Destabilising)** |
| Job ID | 177992502783 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992502783 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/03 00:00 |
| Inheritance | WFS1 spectrum. |
| WFS1 variant landscape | R456H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders

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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| 1.26. AlphaMissense 0.16 below threshold but multi-phenotype + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism: partial charge loss from R456-R457 cluster + E452 salt-bridge disruption. Therapeutic: same loop as R457S.

**Why this card matters.** R456H + R457S — adjacent variants in 456-457 charged cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R456H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 456 with ball-and-stick + neighbors within 5Å)
- `R456H_variant_card.md` — this card (source of truth)
- `R456H_variant_card.html` — styled printable card
- `R456H_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)
- `R456H_wildtype_interactions.pse` / `R456H_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.*