# WFS1 Wolframin — L734H Variant Card

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

*Leucine → Histidine at position 734 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.461 (below threshold), ΔΔG -0.47.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L734H (p.Leucine734Histidine) |
| **DNA change** | c.2201T>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000593953 |
| **Amino acid change** | Leucine (L) → Histidine (H) — branched aliphatic replaced by aromatic titratable basic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 734** | **87.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 734 (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 734 in lumenal domain — same C733-C765 disulfide region (R732C, C733G, C765R). Neighbors: TYR735 (2.5 Å — Y735 partner of G736 environment), CYS733 (2.5 Å — the C733 disulfide cysteine!), MET731 (3.8 Å), TRP730 (3.8 Å).

L734H sits immediately downstream of C733 — perturbing the C733-C765 disulfide region from the adjacent position. AM 0.461 below threshold but Wolfram 1 confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4608** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.47 (Destabilising)** |
| Job ID | 177992472967 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992472967 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2017/09/26 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | L734H 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.47. AlphaMissense 0.461 below threshold but Wolfram 1 confirms pathogenicity.<br/><br/>Mechanism: perturbation of C733-C765 disulfide region from adjacent position. Therapeutic: same C733-C765 microregion.

**Why this card matters.** L734H is in the same C733-C765 disulfide microregion as R732C, C733G, C765R.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L734H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 734 with ball-and-stick + neighbors within 5Å)
- `L734H_variant_card.md` — this card (source of truth)
- `L734H_variant_card.html` — styled printable card
- `L734H_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)
- `L734H_wildtype_interactions.pse` / `L734H_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.*