# WFS1 Wolframin — R818C Variant Card

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

*Arginine → Cysteine at position 818 in lumenal domain. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.38 (below threshold), DynaMut2 ΔΔG +0.24 kcal/mol (mild stabilising). Another R→C class variant with free-thiol risk.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R818C (p.Arginine818Cysteine) |
| **DNA change** | c.2452C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000130748 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — long positively-charged guanidinium replaced by short thiol-bearing residue. Loss of charge plus introduction of potential aberrant disulfide site. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 818** | **85.81** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 818 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
  - Natural variant: 818-818 in WFS1; dbSNP:rs35932623

> Position 818 sits in wolframin's C-terminal lumenal domain. Neighbors: GLN819 (2.4 Å — same Q819 contacted by K705N/E across the fold!), LEU817 (2.5 Å), SER821 (4.4 Å — same S821 contacted by R703C across the fold). The Q819 and S821 contacts are structurally significant — R818 sits in a long-range contact network with the R705-Q819 microregion.

Replacing R818 with cysteine eliminates the positive charge contributing to the Q819 contact and introduces a free thiol into the oxidizing ER lumen. The new C818 could engage in aberrant disulfide chemistry with nearby cysteines (no immediate cysteine partners within 5 Å, but the lumenal domain has multiple cysteines that could be reached).

The ΔΔG of +0.24 is mild stabilising — the fold packs efficiently with the smaller cysteine. AlphaMissense's 0.38 is below threshold (AM under-call). Multi-phenotype clinical evidence (monogenic diabetes + WFS1 spectrum) confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3822** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.24 (Stabilising)** |
| Job ID | 177992477338 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992477338 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/01 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | R818C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- 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 4 — Stable Fold, Function Disrupted (AM under-call).</strong> ΔΔG +0.24 stabilising. AlphaMissense 0.38 below threshold but multi-phenotype clinical confirms pathogenicity.<br/><br/>Mechanism: loss of R818 charge from Q819-S821 long-range contact network + free-thiol introduction with aberrant disulfide risk. Therapeutic strategy: site-directed at the Q819 microregion (shared with K705N/E).

**Why this card matters.** R818C joins the growing R→C disulfide-risk class. The Q819 long-range contact links this variant to the K705 region — convergent multi-variant target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R818C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 818 with ball-and-stick + neighbors within 5Å)
- `R818C_variant_card.md` — this card (source of truth)
- `R818C_variant_card.html` — styled printable card
- `R818C_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)
- `R818C_wildtype_interactions.pse` / `R818C_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.*