# WFS1 Wolframin — V412L Variant Card

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

*Valine → Leucine at position 412 inside TM3. ClinVar Conflicting. AlphaMissense 0.663, ΔΔG -0.47. Same position as V412A. Conservative branched-aliphatic swap.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | V412L (p.Valine412Leucine) |
| **DNA change** | c.1234G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000143131 |
| **Amino acid change** | Valine (V) → Leucine (L) — branched aliphatic to branched aliphatic. Modest volume increase. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 412** | **93.69** — well-folded |
| **Domain** | TM3 (402-422), helical transmembrane |
| **Position context** | TM3 (residues 402–422) · position 412 (pLDDT 94). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 402-422 Helical

> Position 412 in TM3. Neighbors: PHE413 (2.5 Å), SER411 (2.5 Å), LEU409 (3.8 Å), PHE408 (3.9 Å — TM3-TM7 interface position).

Replacing V412 with leucine is the most conservative substitution at this position. Yet ΔΔG -0.47 + AM 0.663 + WFS1 spectrum confirm pathogenicity. Mechanism is volume mismatch with surrounding F413, S411 environment and perturbation of the F408 TM3-TM7 contact.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6632** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.47 (Destabilising)** |
| Job ID | 177992466151 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992466151 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/09/23 00:00 |
| Inheritance | WFS1 spectrum. |
| WFS1 variant landscape | V412L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- WFS1-Related Spectrum Disorders

---

## 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| = 0.47. AlphaMissense 0.663 confirms pathogenicity.<br/><br/>Mechanism: conservative volume mismatch in TM3 + F408 interface perturbation. Therapeutic: TM3-TM7 interface.

**Why this card matters.** V412L + V412A at same position — both pathogenic despite extremely conservative chemistry. Position 412 in TM3 is structurally inflexible.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V412L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 412 with ball-and-stick + neighbors within 5Å)
- `V412L_variant_card.md` — this card (source of truth)
- `V412L_variant_card.html` — styled printable card
- `V412L_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)
- `V412L_wildtype_interactions.pse` / `V412L_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*