# WFS1 Wolframin — L187F Variant Card

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

*Leucine → Phenylalanine at position 187 in wolframin's N-terminal cytoplasmic domain. ClinVar Pathogenic/Likely pathogenic with broad clinical spectrum — Cataract 41, Wolfram-like syndrome, DFNA6. AlphaMissense 0.954, DynaMut2 ΔΔG -1.42 kcal/mol (destabilising). A conservative-looking substitution with substantial structural cost.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L187F (p.Leucine187Phenylalanine) |
| **DNA change** | c.559C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002193625 |
| **Amino acid change** | Leucine (L) → Phenylalanine (F) — a medium-sized branched hydrophobic replaced by a larger aromatic hydrophobic. Volume increase plus π-electron system added. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 187** | **83.50** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 187 sits in the cytosol-facing region of wolframin with good AlphaFold confidence (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 187 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places L187 within 5 Å of ASN188 (2.5 Å), LYS186 (2.5 Å), TYR184 (3.6 Å), MET183 (3.9 Å), and ASN203 (4.1 Å). The local environment is mixed — aromatic (Y184), polar (N188, N203), basic (K186), and hydrophobic (M183, L187 itself).

Replacing leucine with phenylalanine at this position is more disruptive than the chemistry pair suggests. Phenylalanine is roughly 50% larger by side-chain volume and introduces an aromatic ring where leucine had only branched aliphatic carbons. The local pocket — packed against TYR184 (3.6 Å) and MET183 (3.9 Å) — was sized for leucine. Adding a phenyl ring forces local rearrangement.

The |ΔΔG| of 1.42 kcal/mol reflects this volume mismatch. The fold absorbs the substitution but at meaningful energetic cost. The introduced aromatic ring also creates a new potential π-π stacking opportunity with TYR184 — but at a geometry not optimized for it in the wild-type fold, so this contact may or may not form productively.

The clinical breadth — Cataract 41, Wolfram-like syndrome, DFNA6 hearing loss — confirms severe functional consequence across multiple tissue contexts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9538** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.42 (Destabilising)** |
| Job ID | 177991404378 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991404378 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2024/04/16 00:00 |
| Inheritance | Autosomal dominant pattern indicated by association with DFNA6 (WFS1-related hearing loss) and Wolfram-like syndrome. |
| WFS1 variant landscape | L187F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Wolfram-like syndrome
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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| = 1.42 kcal/mol — meaningful but below the Cat 2 threshold. AlphaMissense 0.954 + three documented clinical phenotypes confirm severe functional consequence.<br/><br/>The mechanism is volume mismatch in a cytoplasmic packing pocket (TYR184, MET183 environment). Therapeutic strategy: site-directed binders that occupy the disrupted packing region, or pharmacological chaperones biasing the fold toward the wild-type leucine geometry.<br/><br/>The clinical breadth (three phenotypes across both AD and tissue-specific presentations) makes this a high-value docking target.

**Why this card matters.** L187F demonstrates that 'conservative' substitutions in chemistry tables can be structurally non-conservative — what looks like a small change in side-chain class (aliphatic to aromatic) becomes substantial when packed into a pocket that wasn't sized for the larger residue. The Atlas's neighbor analysis surfaces the specific contacts (TYR184, MET183) that the substitution perturbs, making the geometric target visible.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L187F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 187 with ball-and-stick + neighbors within 5Å)
- `L187F_variant_card.md` — this card (source of truth)
- `L187F_variant_card.html` — styled printable card
- `L187F_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)
- `L187F_wildtype_interactions.pse` / `L187F_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.*