# WFS1 Wolframin — A58T Variant Card

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

*Ala→Thr p58 IDR AM=0.08 ddg=+0.05 pLDDT=26. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A58T (p.Alanine58Threonine) |
| **DNA change** | c.172G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000393384 |
| **Amino acid change** | polarity into IDR |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 58** | **26.17** — **IDR (below 50 threshold)** |
| **Domain** | N-terminal intrinsically disordered region (1-86) |
| **Position context** | N-terminal IDR |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Region: 1-86 Disordered
  - Natural variant: 58-58 in WFS1; dbSNP:rs369671890

> Position analysis: ALA59 (2.5 Å), ALA57 (2.5 Å). pLDDT 26 deep IDR. Third substitution near 57-58 cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0769** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.05 (Stabilising)** |
| Job ID | 177992519804 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992519804 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2021/11/02 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | A58T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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 5 — IDR Exclusion**

<strong>Cat 5 IDR — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

**Why this card matters.** Position 57-58 IDR multi-substitution.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A58T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 58 with ball-and-stick + neighbors within 5Å)
- `A58T_variant_card.md` — this card (source of truth)
- `A58T_variant_card.html` — styled printable card
- `A58T_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)
- `A58T_wildtype_interactions.pse` / `A58T_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.*