# WFS1 Wolframin — P885L Variant Card

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

*Proline → Leucine at position 885 inside wolframin's eleventh and final transmembrane helix (TM11). ClinVar Pathogenic/Likely pathogenic with the broadest clinical spectrum documented for any single position in the gene: Wolfram syndrome 1, Wolfram-like syndrome, DFNA6 hearing loss, Cataract 41, type 2 diabetes. AlphaMissense 0.971, DynaMut2 ΔΔG -0.50 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P885L (p.Proline885Leucine) |
| **DNA change** | c.2654C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000437297 |
| **Amino acid change** | Proline (P) → Leucine (L) — a rigid, ring-locked, helix-breaking residue replaced by a flexible, branched hydrophobic. The substitution removes a deliberate helix kink from a transmembrane segment. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 885** | **74.19** — well-folded |
| **Domain** | TM11 (870-890), helical transmembrane |
| **Position context** | TM11 (residues 870–890) · position 885 is bilayer-embedded near the C-terminus of wolframin, where TM11 anchors the lumenal domain to the membrane. pLDDT 74 indicates good local confidence in the AlphaFold model. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 870-890 Helical
  - Natural variant: 885-885 in WFS1; mild form; dbSNP:rs372855769

> Position 885 sits inside TM11, the final transmembrane helix of wolframin. The AlphaFold model places P885 within 5 Å of PHE886 (2.5 Å), PHE884 (2.5 Å), PHE883 (4.2 Å), and LEU887 (4.7 Å). The local environment is dominated by aromatic residues — an aromatic cluster (F883, F884, F886) within a single membrane-embedded turn of helix.

The wild-type proline at position 885 is structurally deliberate. Proline residues in transmembrane helices appear in specific positions where the protein needs the helix to kink — they introduce a controlled bend in what would otherwise be a straight α-helix. Proline at position 885, sitting in the middle of three consecutive phenylalanines, almost certainly serves this kinking role: it creates a controlled local geometry that the surrounding aromatic packing depends on.

Replacing proline with leucine removes that controlled kink. Leucine cannot break the helix in the same way — its backbone is free to adopt the standard α-helical phi/psi angles. The result is a TM11 that is more linear than the wild-type, with the aromatic cluster (F883, F884, F886) reorganized accordingly. The interlocking packing that depends on the wild-type kink is lost.

The |ΔΔG| of 0.50 kcal/mol indicates the fold absorbs this rearrangement — TM11 still embeds in the membrane, the protein still folds. But the precise geometry of the C-terminal anchoring region is changed, and the AlphaMissense score of 0.971 reflects severe functional consequence. Notably, C505Y (Atlas card adjacent, in TM6) has PRO885 as a 4.1 Å neighbor — suggesting TM6-TM11 cross-talk in the membrane. Disrupting the P885 kink also affects whatever functional contact TM6 makes through this position.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9711** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.5 (Destabilising)** |
| Job ID | 177991404199 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991404199 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/06/04 00:00 |
| Inheritance | Both autosomal dominant (DFNA6, Wolfram-like) and autosomal recessive (Wolfram syndrome 1) forms documented. The breadth of clinical conditions makes this one of the most clinically impactful variants in the Atlas. |
| WFS1 variant landscape | P885L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Wolfram-like syndrome
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)
- Cataract 41
- Type 2 diabetes mellitus

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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| = 0.50 kcal/mol — fold survives. AlphaMissense 0.971 + five documented clinical phenotypes confirm severe functional consequence.<br/><br/>The mechanism is loss of a deliberate proline-induced helix kink in TM11, perturbing the C-terminal membrane anchoring geometry and disrupting the TM6-TM11 cross-helix contact through C505/P885 (see C505Y Atlas card for the reciprocal view).<br/><br/>The therapeutic strategy is site-directed at the TM11 aromatic cluster: a small molecule that restores the helix geometry the wild-type kink produced, or that occupies the disrupted TM6-TM11 interface, would compensate for the lost kink. The clinical breadth (five distinct phenotypes documented) makes this one of the highest-value docking targets in the WFS1 atlas.

**Why this card matters.** P885L exemplifies how the atlas's structural reasoning surfaces non-obvious therapeutic targets. The variant's pathogenicity is well-established clinically; what was not visible without the structural map is that TM11's geometry depends on a deliberate proline kink, and disrupting it perturbs the TM6-TM11 interface across the membrane. C505Y in the Atlas points back to this same interface from the TM6 side. A drug aimed at the TM6-TM11 contact rescues both variants — and likely several others in the same region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P885L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 885 with ball-and-stick + neighbors within 5Å)
- `P885L_variant_card.md` — this card (source of truth)
- `P885L_variant_card.html` — styled printable card
- `P885L_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)
- `P885L_wildtype_interactions.pse` / `P885L_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.*