# WFS1 Wolframin — W639G Variant Card

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

*Tryptophan → Glycine at position 639 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic. AlphaMissense 0.481 (BELOW the likely-pathogenic threshold), DynaMut2 ΔΔG -1.03 kcal/mol (destabilising). A variant where the structural cost is clear but the AlphaMissense signal is unexpectedly weak.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | W639G (p.Tryptophan639Glycine) |
| **DNA change** | c.1915T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003720568 |
| **Amino acid change** | Tryptophan (W) → Glycine (G) — bulky aromatic replaced by the smallest amino acid. Massive volume loss; aromatic character entirely eliminated. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 639** | **86.50** — well-folded |
| **Domain** | TM10 (632-652), helical transmembrane |
| **Position context** | TM10 (residues 632–652) · position 639 is in the middle of TM10, bilayer-embedded (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 632-652 Helical

> Position 639 sits in the middle of TM10. The AlphaFold model places W639 within 5 Å of VAL638 (2.5 Å), LEU640 (2.5 Å), ILE636 (3.6 Å), LEU635 (3.8 Å), and ALA642 (4.3 Å). The local environment is uniformly hydrophobic — an aliphatic-rich pocket where the wild-type tryptophan's bulky indole ring contributes substantial volume.

Replacing tryptophan with glycine removes the indole ring entirely, leaving a small cavity in the TM10 hydrophobic core. The DynaMut2 |ΔΔG| of 1.03 captures this — the volume mismatch produces meaningful destabilization, larger than most variants in this batch.

Yet AlphaMissense places this at 0.481 — below the 0.564 likely-pathogenic threshold. AM considers this variant likely benign. The discrepancy with ClinVar Pathogenic classification is striking.

Two interpretations: (1) AM's training data may under-represent TM-helix variants in general, leading to systematic under-calling of pathogenicity in this structural context; (2) The variant may be technically pathogenic in specific clinical scenarios (compound heterozygosity, specific tissue contexts) but not in the more general population-genetics sense AM is trained on. The DynaMut2 destabilization (|ΔΔG| 1.03) is real and substantial.

This is a variant where ΔΔG is informative and AM is uncertain.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4809** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.03 (Destabilising)** |
| Job ID | 177990266823 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990266823 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/10/03 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | W639G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for W639G — ClinVar Pathogenic by review evidence)

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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 caveat).</strong> |ΔΔG| = 1.03 kcal/mol — fold absorbs the substitution at meaningful cost. AlphaMissense 0.481 is below the likely-pathogenic threshold but ClinVar Pathogenic classification is established.<br/><br/>The mechanism is volume loss in a TM10 hydrophobic packing pocket — the lost tryptophan indole creates a cavity that destabilizes the local membrane-embedded geometry. Therapeutic strategy: site-directed small molecules that fill the cavity left by W639, restoring the wild-type packing volume.<br/><br/>The unexpected AM signal mismatch is itself a finding the Atlas surfaces — variants where structural destabilization is clear but AM training under-calls pathogenicity exist, and they deserve wet-lab characterization to clarify mechanism.

**Why this card matters.** W639G demonstrates the value of the Atlas's dual-metric framing in the opposite direction from variants like T361I. Where T361I has stabilising ΔΔG but high AM (functional mechanism), W639G has destabilising ΔΔG but low AM (structural mechanism not captured by AM training). The Atlas captures both — the framework is more complete than either metric alone.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `W639G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 639 with ball-and-stick + neighbors within 5Å)
- `W639G_variant_card.md` — this card (source of truth)
- `W639G_variant_card.html` — styled printable card
- `W639G_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)
- `W639G_wildtype_interactions.pse` / `W639G_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.*