# WFS1 Wolframin — R685P Variant Card

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

*Arginine → Proline at position 685 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with rare genetic deafness. AlphaMissense 0.954, DynaMut2 ΔΔG +0.33 kcal/mol — a STABILIZING substitution. A charge-loss-plus-helix-break variant.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R685P (p.Arginine685Proline) |
| **DNA change** | c.2054G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045446 |
| **Amino acid change** | Arginine (R) → Proline (P) — a large, positively-charged guanidinium-bearing residue replaced by a rigid, helix-breaking residue. Loss of charge and side chain volume; introduction of backbone constraint. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 685** | **89.94** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 685 in the ER lumen with high AlphaFold confidence (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 685-685 in DFNA6; dbSNP:rs142668478

> Position 685 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places R685 within 5 Å of THR686 (2.5 Å), ALA684 (2.5 Å — the partner residue in the A684T atlas card), ASN682 (3.5 Å), MET683 (4.3 Å), and GLN687 (4.4 Å). The wild-type arginine's long, positively-charged side chain likely makes H-bond contacts with the nearby polar residues (N682, T686, Q687).

Replacing arginine with proline at 685 removes the long side chain and introduces a rigid ring-locked residue. The H-bond network the wild-type R685 maintained is gone; the local backbone gains a forced kink from the proline. The DynaMut2 ΔΔG of +0.33 (stabilising) reflects that the tighter local packing achievable with proline outweighs the lost H-bonding in pure energetic terms.

Yet the variant is pathogenic — AlphaMissense 0.954, ClinVar Pathogenic, associated with rare genetic deafness. The pathogenic mechanism is functional: the lost R685 H-bond network is required for wolframin's lumenal function (likely partner protein recognition), even though the fold accommodates the substitution structurally.

Notably, A684T sits at the adjacent position with its own Atlas card — a second variant in the same microregion. Both R685P and A684T perturb the M683-A684-R685-T686 loop geometry, just from different sides.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9540** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.33 (Stabilising)** |
| Job ID | 177990263652 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990263652 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2012/02/28 00:00 |
| Inheritance | Documented in association with rare genetic deafness. AD-leaning presentation pattern likely. |
| WFS1 variant landscape | R685P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Rare genetic deafness

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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 3/4 — Most Druggable**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.33 kcal/mol — actively stabilising. AlphaMissense 0.954 + clinical evidence confirm pathogenicity.<br/><br/>The mechanism is functional rather than structural: lost R685 H-bond network with N682, T686, Q687, plus introduction of a backbone kink from proline. Drug discovery here aims at the functional contact, not at fold rescue.<br/><br/>Combined with A684T (Atlas card adjacent), drug discovery in the 683-687 microregion has two convergent variant targets.

**Why this card matters.** R685P is another Atlas variant where ΔΔG is positive (stabilising) but the variant is unambiguously pathogenic — joining T361I, L402P in this class. These variants are invisible to ΔΔG-only analysis but clearly picked up by AlphaMissense and clinical evidence. They are exactly the variants the Atlas's dual-metric framing was designed to surface.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R685P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 685 with ball-and-stick + neighbors within 5Å)
- `R685P_variant_card.md` — this card (source of truth)
- `R685P_variant_card.html` — styled printable card
- `R685P_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)
- `R685P_wildtype_interactions.pse` / `R685P_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.*