# WFS1 Wolframin — A133T Variant Card

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

*Alanine → Threonine at position 133 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram-like + Cataract 41. AlphaMissense 0.878, ΔΔG -1.83 (close to Cat 2 boundary).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A133T (p.Alanine133Threonine) |
| **DNA change** | c.397G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001331467 |
| **Amino acid change** | Alanine (A) → Threonine (T) — small methyl-bearing hydrophobic replaced by small polar hydroxyl. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 133** | **92.00** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 133 (pLDDT 92). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Natural variant: 133-133 in WFS1; dbSNP:rs372249044

> Position 133 sits in cytoplasmic domain. Neighbors: LEU132 (2.5 Å), ALA134 (2.5 Å), GLN103 (3.5 Å — long-range), LEU130 (3.8 Å). Adjacent to A126T microregion (A126T at 4.5 Å away in sequence; both in same broader cytoplasmic pocket).

Replacing A133 with threonine introduces polarity into a hydrophobic cytoplasmic pocket. The Q103 long-range contact at 3.5 Å suggests the variant T133 hydroxyl could H-bond with Q103, but the geometric cost is substantial. |ΔΔG| 1.83 close to Cat 2 threshold reflects this.

AlphaMissense 0.878 + Wolfram-like + Cataract 41 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8780** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.83 (Destabilising)** |
| Job ID | 177992460997 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992460997 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/05 00:00 |
| Inheritance | Wolfram-like + Cataract 41 documented. |
| WFS1 variant landscape | A133T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome
- 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 (near Cat 2 boundary).</strong> |ΔΔG| = 1.83 — closest to Cat 2 threshold in this batch. AlphaMissense 0.878 confirms severe consequence.<br/><br/>Mechanism: polarity introduction into a hydrophobic cytoplasmic pocket. Therapeutic: same N-terminal microregion as A126T (close in sequence and structure).

**Why this card matters.** A133T + A126T together establish the 126-133 cytoplasmic microregion as a multi-variant target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A133T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 133 with ball-and-stick + neighbors within 5Å)
- `A133T_variant_card.md` — this card (source of truth)
- `A133T_variant_card.html` — styled printable card
- `A133T_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)
- `A133T_wildtype_interactions.pse` / `A133T_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.*