# WFS1 Wolframin — W399G Variant Card

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

*Tryptophan → Glycine at position 399 in a connecting loop. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.713, ΔΔG -1.06. Bulky aromatic → smallest amino acid.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | W399G (p.Tryptophan399Glycine) |
| **DNA change** | c.1195T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215386 |
| **Amino acid change** | Tryptophan (W) → Glycine (G) — bulky aromatic indole replaced by smallest amino acid. Massive volume loss. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 399** | **76.44** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 399 (pLDDT 76). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 399 in connecting loop. Neighbors: ASN400 (2.5 Å), GLY398 (2.5 Å — adjacent existing glycine!), ASN396 (3.9 Å), VAL395 (4.0 Å — near E394V).

Replacing W399 with glycine creates G398-G399 double-glycine motif (extra backbone flexibility) and removes the aromatic side chain entirely. Two adjacent glycines in a loop produce unusual conformational freedom. ΔΔG 1.06 reflects this. AM 0.713 + Cataract 41 + DFNA6 confirm severe consequence.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7125** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.06 (Destabilising)** |
| Job ID | 177992465049 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992465049 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/04 00:00 |
| Inheritance | AD: DFNA6 + Cataract 41. |
| WFS1 variant landscape | W399G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

---

## 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| = 1.06. AlphaMissense 0.713 + dual phenotypes confirm severe consequence.<br/><br/>Mechanism: massive volume loss + creation of G398-G399 double-glycine motif. Therapeutic: loop region site-directed.

**Why this card matters.** W399G is in the same 392-399 loop region as E394V — multi-variant target cluster.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `W399G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 399 with ball-and-stick + neighbors within 5Å)
- `W399G_variant_card.md` — this card (source of truth)
- `W399G_variant_card.html` — styled printable card
- `W399G_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)
- `W399G_wildtype_interactions.pse` / `W399G_mutant_interactions.pse` — PyMOL sessions

---

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