# WFS1 Wolframin — G107E Variant Card

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

*Glycine → Glutamate at position 107 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic, associated with classical autosomal recessive Wolfram syndrome 1. AlphaMissense 0.993, DynaMut2 ΔΔG -1.51 kcal/mol (destabilising). The Atlas's strongest N-terminal cytoplasmic variant — a region where most pathogenic variants until now have not had structural characterization.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G107E (p.Glycine107Glutamate) |
| **DNA change** | c.320G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000982858 |
| **Amino acid change** | Glycine (G) → Glutamate (E) — the smallest amino acid (no side chain, only backbone flexibility) replaced by a negatively-charged carboxylate-bearing residue. The substitution introduces both volume and charge where the wild-type provided neither. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 107** | **93.00** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain (residues 87–313) · position 107 sits in wolframin's cytosolic regulatory region in a high-confidence local environment (pLDDT 93). The cytosol's aqueous environment is compatible with charged side chains, but glycine's role in this position is unusual. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Natural variant: 107-107 

> Position 107 sits in wolframin's N-terminal cytoplasmic domain, the region facing the cytosol where the protein engages cytosolic regulatory partners. The AlphaFold model places G107 within 5 Å of VAL106 (2.5 Å), LYS108 (2.5 Å), THR104 (3.7 Å), GLN103 (3.8 Å), TRP129 (4.0 Å — a longer-range contact), and ALA126 (4.0 Å). The local environment is mixed polar-hydrophobic, consistent with a cytosolic protein surface.

The wild-type glycine at 107 is structurally meaningful — glycine is the only amino acid with no side chain, which allows backbone conformations (especially in the Ramachandran 'left-handed helix' region) that other amino acids cannot adopt. Glycines in specific positions enable backbone flexibility that other residues constrain. Position 107's glycine, sitting between V106 and K108 and contacting TRP129 across a structural element, plausibly provides exactly this flexibility — allowing the local backbone to adopt a configuration that other amino acids cannot.

Replacing glycine with glutamate has two layered structural costs. First, the backbone is now constrained by the glutamate side chain's steric requirements — the local conformation cannot adopt the wild-type glycine geometry. Second, the introduced carboxylate adds negative charge to a position where the wild-type contributed none. Combined, these produce a |ΔΔG| of 1.51 kcal/mol — substantial for a cytosolic position, reflecting both the lost backbone flexibility and the steric-plus-electrostatic accommodation needed.

AlphaMissense's 0.993 score reflects the high pathogenic potential of removing a structurally critical glycine. The variant is one of the few in this batch where both the structural cost (relatively high |ΔΔG|) and the functional cost (high AM) are clearly visible — a coherent Category 3/4 signature.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9926** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.51 (Destabilising)** |
| Job ID | 177991411014 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991411014 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2019/01/01 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented in ClinVar. |
| WFS1 variant landscape | G107E is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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| = 1.51 kcal/mol — meaningful destabilization but still well within the fold-intact range. AlphaMissense 0.993 confirms severe functional consequence.<br/><br/>The mechanism is loss of backbone flexibility (the wild-type glycine enabled a backbone conformation the mutant glutamate cannot) plus the addition of negative charge into a structurally constrained position. The therapeutic strategy is site-directed: a small molecule that stabilizes the local fold against the variant's preferred (and incorrect) conformation, biasing the population toward functional protein.<br/><br/>This is one of the few N-terminal cytoplasmic variants in the Windsor Set with full atlas characterization. Most pathogenic N-terminal variants in WFS1 have not had structural analysis at this resolution. The atlas brings that resolution to the cytosolic domain for the first time.

**Why this card matters.** G107E is one of the Atlas's clearest demonstrations of glycine's structural role. Removing glycine constrains backbone flexibility in ways that other amino-acid swaps don't. Drug discovery targeting variants of this class works at the conformational equilibrium level: a chaperone or small-molecule binder biases the local fold toward the wild-type geometry the glycine enabled. This mechanism class — "glycine-removal" — appears at multiple positions across the WFS1 atlas and represents a coherent therapeutic target category.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G107E_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 107 with ball-and-stick + neighbors within 5Å)
- `G107E_variant_card.md` — this card (source of truth)
- `G107E_variant_card.html` — styled printable card
- `G107E_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)
- `G107E_wildtype_interactions.pse` / `G107E_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.*