# WFS1 Wolframin — R629W Variant Card

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

*Arginine → Tryptophan at position 629 in a connecting loop. ClinVar Pathogenic, associated with classical Wolfram syndrome 1. AlphaMissense 0.181 (deep BENIGN range), DynaMut2 ΔΔG -0.56 kcal/mol (destabilising). pLDDT 60 — borderline. A puzzling variant: ClinVar says pathogenic, AM says benign, ΔΔG is mild.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R629W (p.Arginine629Tryptophan) |
| **DNA change** | c.1885C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001071979 |
| **Amino acid change** | Arginine (R) → Tryptophan (W) — large positively-charged guanidinium-bearing residue replaced by bulky aromatic indole-bearing residue. Loss of charge, gain of aromatic packing. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 629** | **59.97** — confident |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 629 sits in a loop region with borderline AlphaFold confidence (pLDDT 60). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Natural variant: 629-629 in WFS1; dbSNP:rs71530910

> Position 629 sits in a connecting loop region. The AlphaFold model places R629 within 5 Å of THR628 (2.5 Å), SER630 (2.5 Å), SER626 (3.8 Å), SER631 (4.3 Å), and LEU627 (4.5 Å). The local environment is unusually serine-rich (S630, S626, S631) — three serines within 5 Å — suggesting a polar loop region characterized by hydroxyl-mediated H-bonding.

The wild-type arginine at 629 likely engages this serine-rich environment through its long, basic side chain — H-bonding to the serine hydroxyls and possibly extending toward a partner protein for recognition.

Replacing arginine with tryptophan eliminates the positive charge and the long H-bond-donating side chain, replacing them with a bulky aromatic indole. The serine-rich local environment loses its arginine partner; the introduced tryptophan does not fit cleanly into a polar pocket.

The |ΔΔG| of 0.56 is modest. But AlphaMissense places this at 0.181 — deep in the likely-benign range. The discrepancy with ClinVar Pathogenic classification (associated with Wolfram syndrome 1) is similar to the W639G case. Possible explanations: AM under-calls pathogenicity for variants in low-confidence regions (pLDDT 60 here); the variant is pathogenic only in specific clinical contexts; or it has been clinically misclassified. The Atlas surfaces this complexity rather than resolving it.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1805** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.56 (Destabilising)** |
| Job ID | 177990266609 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990266609 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/10/17 00:00 |
| Inheritance | Documented in association with Wolfram syndrome 1 (AR). |
| WFS1 variant landscape | R629W is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Inborn genetic diseases

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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 4 — Stable Fold, Function Disrupted (AM caveat).</strong> |ΔΔG| = 0.56 kcal/mol — fold survives. AlphaMissense 0.181 deep benign — but ClinVar Pathogenic.<br/><br/>The mechanism, if pathogenic, is loss of an arginine-serine network in a polar loop region. Therapeutic strategy is genuinely uncertain given the AM-ClinVar disconnect and the pLDDT 60 borderline structural confidence.<br/><br/>This is a variant where wet-lab characterization is strongly recommended before any therapeutic strategy is set. The Atlas appropriately flags the conflict rather than over-confidently picking a side.

**Why this card matters.** R629W is one of the Atlas's clearest "gray zone" variants. AM says benign, ClinVar says pathogenic, pLDDT is borderline, ΔΔG is mild. The Atlas surfaces this conflict honestly. Drug discovery here pauses; experimental validation drives the next step. The framework's value here is in NOT committing to a confident interpretation when the evidence doesn't support one.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R629W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 629 with ball-and-stick + neighbors within 5Å)
- `R629W_variant_card.md` — this card (source of truth)
- `R629W_variant_card.html` — styled printable card
- `R629W_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)
- `R629W_wildtype_interactions.pse` / `R629W_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.*