# WFS1 Wolframin — G674W Variant Card

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

*Glycine → Tryptophan at position 674 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.991, DynaMut2 ΔΔG -0.77 kcal/mol (destabilising). The largest substitution at position 674 — backbone flexibility loss combined with massive volume increase.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G674W (p.Glycine674Tryptophan) |
| **DNA change** | c.2020G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003618121 |
| **Amino acid change** | Glycine (G) → Tryptophan (W) — the smallest amino acid replaced by the largest (bulky aromatic indole). Maximum volume contrast in protein chemistry. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 674** | **84.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 674 in the ER lumen (pLDDT 84). Same environment as G674E, G674R. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 674-674 in dbSNP:rs200672755

> Position 674 sits in wolframin's C-terminal lumenal domain, between CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), and ARG676 (4.5 Å). The TRP678 contact at 4.0 Å is structurally significant: an existing tryptophan four residues downstream in the chain.

Replacing glycine with tryptophan at position 674 has two simultaneous costs. First, the glycine backbone flexibility is gone — the local conformation must rearrange to accommodate any non-glycine residue. Second, the introduced indole ring is roughly an order of magnitude larger than glycine's missing side chain. The local pocket simply does not have space for a tryptophan in the wild-type geometry; substantial local rearrangement is forced.

The combination produces a |ΔΔG| of 0.77 kcal/mol — comparable to G674R's 0.83, both larger than G674E's 0.34. The fold absorbs the substitution, but at meaningful cost. The new W674 plus the existing W678 creates a two-tryptophan cluster in the loop, which might engage in π-stacking with each other in the variant's rearranged geometry — but this is an artifact of the mutation, not a functional feature.

AlphaMissense's 0.991 score confirms severe functional consequence. The pathogenicity mechanism is the same as G674E/G674R: removal of glycine flexibility at a position that requires it, plus secondary disruption from the specific introduced residue's properties.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9908** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.77 (Destabilising)** |
| Job ID | 177990254299 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990254299 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/07/23 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic classification establishes clinical relevance. |
| WFS1 variant landscape | G674W is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for G674W — 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.77 kcal/mol — fold survives. AlphaMissense 0.991 confirms severe functional consequence.<br/><br/>The mechanism combines glycine flexibility loss (shared across the G674E/R/W series) with volume mismatch (specific to G674W). Therapeutic strategy: same backbone-geometry stabilization as G674E and G674R. A drug aimed at the position 674 microregion targets all three known substitutions.<br/><br/>The G674W variant's introduced aromatic ring could be exploited by a drug designed to displace the variant tryptophan back into a wild-type-like geometry — a selective rescue strategy that wouldn't work for G674E or G674R.

**Why this card matters.** G674W completes the three-substitution series at position 674. Together with G674E (charge introduction) and G674R (charge introduction, opposite sign), the series demonstrates that glycine's role at this position is essential and irreplaceable — any non-glycine substitution produces pathogenic consequence through the same fundamental mechanism. The Atlas's per-variant analysis surfaces this convergence; pre-atlas studies of individual variants would not have seen the pattern.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G674W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 674 with ball-and-stick + neighbors within 5Å)
- `G674W_variant_card.md` — this card (source of truth)
- `G674W_variant_card.html` — styled printable card
- `G674W_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)
- `G674W_wildtype_interactions.pse` / `G674W_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.*