# WFS1 Wolframin — V871G Variant Card

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

*Valine → Glycine at position 871 inside TM11. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.27 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.76.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V871G (p.Valine871Glycine) |
| **DNA change** | c.2612T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001572110 |
| **Amino acid change** | Valine (V) → Glycine (G) — branched aliphatic replaced by smallest amino acid. Massive cavity creation. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 871** | **74.25** — well-folded |
| **Domain** | TM11 (870-890), helical transmembrane |
| **Position context** | TM11 (residues 870–890) · position 871 at TM11 start (pLDDT 74). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 870-890 Helical
  - Natural variant: 871-871 in dbSNP:rs71532874

> Position 871 at TM11 start. Neighbors: HIS872 (2.5 Å — same H872 as K876T/A874T), THR870 (2.5 Å), TRP867 (3.7 Å — aromatic). The H872-V871-T870-W867 region is the TM11 start.

V871G removes side chain creating cavity in TM11 hydrophobic core. |ΔΔG| 0.76 + AM 0.27 under-call + multi-phenotype confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2680** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.76 (Destabilising)** |
| Job ID | 177992497507 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992497507 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/28 00:00 |
| Inheritance | AD: Cataract + DFNA6. |
| WFS1 variant landscape | V871G 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)

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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| 0.76. AlphaMissense 0.27 below threshold but multi-phenotype confirms pathogenicity.<br/><br/>Mechanism: cavity creation at TM11 start. Therapeutic: TM11 multi-variant cluster.

**Why this card matters.** V871G + V871M at same position. TM11 cluster expands further.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V871G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 871 with ball-and-stick + neighbors within 5Å)
- `V871G_variant_card.md` — this card (source of truth)
- `V871G_variant_card.html` — styled printable card
- `V871G_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)
- `V871G_wildtype_interactions.pse` / `V871G_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.*