# WFS1 Wolframin — V503G Variant Card

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

*Valine → Glycine at position 503 inside TM6. ClinVar Pathogenic for DFNA6 hearing loss. AlphaMissense 0.38 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.88 kcal/mol — close to Cat 2 boundary. Cavity creation in dense TM6 multi-variant cluster.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V503G (p.Valine503Glycine) |
| **DNA change** | c.1508T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002501448 |
| **Amino acid change** | Valine (V) → Glycine (G) — branched aliphatic hydrophobic replaced by smallest amino acid (no side chain). Loss of packing volume entirely. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 503** | **81.44** — well-folded |
| **Domain** | TM6 (496-516), helical transmembrane |
| **Position context** | TM6 (residues 496–516) · position 503 mid-helix, bilayer-embedded (pLDDT 81). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 496-516 Helical

> Position 503 sits in TM6, immediately upstream of P504 (P504L Atlas card) and C505 (C505Y, Y508C Atlas region). Neighbors: SER502 (2.5 Å), PRO504 (2.5 Å), CYS505 (4.3 Å). The TM6 mid-helix region is now extensively characterized in the Atlas — V503G, P504L, C505Y, Y508C all converge here.

Replacing V503 with glycine eliminates the branched aliphatic side chain entirely, creating a substantial cavity in the bilayer-embedded core. The local packing — sized for valine + the surrounding P504 backbone constraint — cannot fill the void without local rearrangement. The TM6-TM11 register through the C505/P885 cross-helix contact (discussed in C505Y, P885L Atlas cards) is perturbed.

The |ΔΔG| of 1.88 — close to the Cat 2 moderate-destabilization threshold — reflects substantial structural cost. AlphaMissense's 0.38 is below the 0.564 pathogenic threshold (AM under-call), but the documented DFNA6 hearing loss plus the substantial ΔΔG confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3770** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.88 (Destabilising)** |
| Job ID | 177992478581 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992478581 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/07 00:00 |
| Inheritance | Autosomal dominant DFNA6 hearing loss documented. |
| WFS1 variant landscape | V503G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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 (near Cat 2 boundary, AM under-call).</strong> |ΔΔG| = 1.88 — closest to Cat 2 threshold in this batch. AlphaMissense 0.38 below threshold but DFNA6 + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism: hydrophobic cavity creation in TM6 plus perturbation of the TM6-TM11 cross-helix register. Therapeutic strategy: same TM6 mid-helix microregion as P504L, C505Y, Y508C — pharmacological chaperone screening warranted given near-Cat-2 stability cost.

**Why this card matters.** V503G is the FOURTH variant in the TM6 mid-helix cluster (with P504L, C505Y, Y508C). All converge on the same therapeutic target geometry. The proximity to P885 (TM11) through the C505 contact means this cluster connects to the TM11 multi-variant region as well — drug discovery here has unusually broad rescue convergence.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V503G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 503 with ball-and-stick + neighbors within 5Å)
- `V503G_variant_card.md` — this card (source of truth)
- `V503G_variant_card.html` — styled printable card
- `V503G_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)
- `V503G_wildtype_interactions.pse` / `V503G_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.*