# WFS1 Wolframin — L432V Variant Card

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

*Leucine → Valine at position 432 inside TM4 — directly adjacent to E431, the lumenal-membrane hub residue. ClinVar Conflicting including WFS1 spectrum + monogenic diabetes. AlphaMissense 0.38 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.36 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L432V (p.Leucine432Valine) |
| **DNA change** | c.1294C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000137913 |
| **Amino acid change** | Leucine (L) → Valine (V) — branched aliphatic replaced by smaller branched aliphatic. Conservative volume reduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 432** | **92.12** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | TM4 (residues 427–447) · position 432 near the lumenal end of TM4 (pLDDT 92). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical

> Position 432 sits at the TM4 lumenal end, immediately downstream of the E431 hub residue. Neighbors: GLU431 (2.5 Å — the multi-variant hub itself), ALA433 (2.5 Å — partner of A433P), CYS429 (3.8 Å). The E431 contact at 2.5 Å is the structurally critical observation: L432V sits in direct contact with the hub that 7+ Atlas variants now converge on (E431Q, S430W, S430L, P428R, A559D, R558C/R558H/A559D microregion).

Replacing L432 with valine is conservative chemistry but the structural cost is substantial — |ΔΔG| 1.36. The wild-type leucine's branched packing supports the precise E431 orientation; reducing the volume to valine shifts the local geometry and perturbs the E431 hub's contact network.

AlphaMissense's 0.38 is below threshold (AM under-call). The multi-phenotype clinical evidence (WFS1 spectrum + monogenic diabetes) plus the substantial ΔΔG confirm pathogenicity. The mechanism is conservative-but-consequential — the type of variant the Atlas's dual-metric framing catches that AM-alone misses.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3803** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.36 (Destabilising)** |
| Job ID | 177992476997 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992476997 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/03/01 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | L432V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders
- Monogenic diabetes

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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| = 1.36 — fold survives at meaningful cost. AlphaMissense 0.38 below threshold but multi-phenotype clinical + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism: subtle volume mismatch immediately adjacent to the E431 hub, perturbing E431's contact network. Therapeutic strategy: same E431 hub target as E431Q, S430W, S430L, P428R, A559D.

**Why this card matters.** L432V is the 8th variant in the E431 hub microregion. Drug discovery at E431 now has unusually dense multi-variant convergence — possibly the highest-leverage docking target in the WFS1 lumenal-membrane interface.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L432V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 432 with ball-and-stick + neighbors within 5Å)
- `L432V_variant_card.md` — this card (source of truth)
- `L432V_variant_card.html` — styled printable card
- `L432V_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)
- `L432V_wildtype_interactions.pse` / `L432V_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.*