# WFS1 Wolframin — V624A Variant Card

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

*Valine → Alanine at position 624 in connecting loop. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.16 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.13 (neutral). pLDDT 47 — IDR boundary.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V624A (p.Valine624Alanine) |
| **DNA change** | c.1871T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000289011 |
| **Amino acid change** | Valine (V) → Alanine (A) — branched aliphatic replaced by small methyl. Volume reduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 624** | **47.38** — **IDR (below 50 threshold)** |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 624 (pLDDT 47 — IDR boundary). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 624 at pLDDT 47 — BELOW the 50 threshold for trustworthy structure. Neighbors: MET623 (2.5 Å), LYS625 (2.5 Å), VAL621 (3.8 Å).

V624A conservative volume reduction in a disordered region. Computational predictions deserve caution. AM 0.16 under-call; WFS1 spectrum documented.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1602** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.13 (Stabilising)** |
| Job ID | 177992502467 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992502467 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/28 00:00 |
| Inheritance | WFS1 spectrum. |
| WFS1 variant landscape | V624A 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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion.</strong> pLDDT 47 below the 50 threshold. AlphaMissense 0.16 below threshold. DynaMut2 prediction not trustworthy.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery.

**Why this card matters.** V624A is another IDR-boundary variant — Atlas appropriately flags.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V624A_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 624 with ball-and-stick + neighbors within 5Å)
- `V624A_variant_card.md` — this card (source of truth)
- `V624A_variant_card.html` — styled printable card
- `V624A_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)
- `V624A_wildtype_interactions.pse` / `V624A_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.*