# WFS1 Wolframin — R138C Variant Card

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

*Arginine → Cysteine at position 138 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.72. R→C class.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R138C (p.Arginine138Cysteine) |
| **DNA change** | c.412C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001000139 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — long positively-charged guanidinium replaced by short thiol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 138** | **89.06** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 138 (pLDDT 89). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 138 in N-term. Neighbors: ARG139 (2.5 Å — adjacent existing arginine), GLY137 (2.5 Å), ALA133 (3.8 Å — A133T position). The wild-type R138 sits adjacent to R139 — two consecutive arginines in the cytoplasmic domain.

R138C eliminates one of the two adjacent positives and introduces a free thiol. In cytosol, the thiol is less reactive than in ER lumen but can still participate in glutathionylation or regulatory thiol chemistry. AM 0.29 under-call; Wolfram 1 confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2891** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.72 (Destabilising)** |
| Job ID | 177992496411 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992496411 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/03/17 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | R138C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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| 0.72. AlphaMissense 0.29 below threshold but Wolfram 1 confirms pathogenicity.<br/><br/>Mechanism: charge loss from R138-R139 cluster + thiol introduction. Therapeutic: same N-term microregion (with A133T adjacent).

**Why this card matters.** R138C joins the R→C class (now 8+ variants) and the 133-138 cytoplasmic cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R138C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 138 with ball-and-stick + neighbors within 5Å)
- `R138C_variant_card.md` — this card (source of truth)
- `R138C_variant_card.html` — styled printable card
- `R138C_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)
- `R138C_wildtype_interactions.pse` / `R138C_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.*