# WFS1 Wolframin — F264L Variant Card

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

*Phenylalanine → Leucine at position 264 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.19 kcal/mol (stabilising). pLDDT 47 — Category 5 IDR territory.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F264L (p.Phenylalanine264Leucine) |
| **DNA change** | c.792C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000504707 |
| **Amino acid change** | Phenylalanine (F) → Leucine (L) — aromatic hydrophobic replaced by branched aliphatic hydrophobic. Aromatic π-system lost. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 264** | **47.03** — **IDR (below 50 threshold)** |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 264 in a borderline-IDR region (pLDDT 47). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

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

> Position 264 sits in wolframin's N-terminal cytoplasmic domain at the boundary of the IDR. pLDDT of 47 is BELOW the 50 threshold — the Atlas formally classifies this position as Category 5 (IDR exclusion). DynaMut2 predictions in this region are not fully trustworthy.

Neighbors: LEU263 (2.5 Å), LEU265 (2.5 Å), SER261 (4.1 Å). The neighbor sparsity is itself an IDR signature.

AlphaMissense's 0.29 is below threshold. The Conflicting ClinVar classifications and the IDR localization together flag this variant as one where computational drug discovery should pause for wet-lab characterization.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2871** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.19 (Stabilising)** |
| Job ID | 177992494543 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992494543 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/06/12 00:00 |
| Inheritance | WFS1-related disorder + Wolfram-like syndrome documented. |
| WFS1 variant landscape | F264L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-related disorder
- Wolfram-like syndrome

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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 (borderline).</strong> pLDDT 47 below the 50 threshold. AlphaMissense 0.29 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.** F264L is the latest Category 5 IDR-region variant in the Atlas. Wet-lab validation required before therapeutic strategy is set.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F264L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 264 with ball-and-stick + neighbors within 5Å)
- `F264L_variant_card.md` — this card (source of truth)
- `F264L_variant_card.html` — styled printable card
- `F264L_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)
- `F264L_wildtype_interactions.pse` / `F264L_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.*