# WFS1 Wolframin — L664R Variant Card

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

*Leucine → Arginine at position 664 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.980, DynaMut2 ΔΔG -0.75 kcal/mol (destabilising). Charge introduction into a hydrophobic position.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L664R (p.Leucine664Arginine) |
| **DNA change** | c.1991T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001705303 |
| **Amino acid change** | Leucine (L) → Arginine (R) — branched aliphatic hydrophobic replaced by large positively-charged guanidinium-bearing residue. Charge introduction into a non-polar environment. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 664** | **84.81** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 664 in the ER lumen (pLDDT 85). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 664 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L664 within 5 Å of THR665 (2.4 Å), THR663 (2.5 Å), GLN668 (3.7 Å — same Q668 as Y669 and L672P environment), SER662 (4.4 Å), and VAL698 (4.9 Å — long-range).

Replacing L664 with arginine introduces a large positive charge into a polar-leaning local environment with H-bonding partners (T665, T663, Q668, S662). The new R664 guanidinium can H-bond with these partners but pulls the local geometry into a new configuration. The Y669-C673-L672-Q668 microregion (densely populated by Atlas variants) is affected.

The |ΔΔG| of 0.75 reflects fold cost. AlphaMissense's 0.980 + Wolfram syndrome 1 confirm severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9796** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.75 (Destabilising)** |
| Job ID | 177992301789 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992301789 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2022/09/23 00:00 |
| Inheritance | Wolfram syndrome 1 documented. |
| WFS1 variant landscape | L664R 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.75 — fold survives. AlphaMissense 0.980 + Wolfram 1 confirm severe functional consequence.<br/><br/>Mechanism is charge introduction into the polar 663-665 microregion that abuts the dense Y669-C673 cluster. Therapeutic strategy: site-directed at the polar microregion adjacent to the Y669 cluster.

**Why this card matters.** L664R sits at the edge of the dense Y669-C673-L672 cluster — close enough that drug discovery in the cluster region likely engages L664 as well.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L664R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 664 with ball-and-stick + neighbors within 5Å)
- `L664R_variant_card.md` — this card (source of truth)
- `L664R_variant_card.html` — styled printable card
- `L664R_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)
- `L664R_wildtype_interactions.pse` / `L664R_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.*