# WFS1 Wolframin — C505Y Variant Card

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

*Cysteine → Tyrosine at position 505 inside wolframin's sixth transmembrane helix (TM6). ClinVar Pathogenic, associated with diabetes mellitus. AlphaMissense 0.892 (deep pathogenic range), DynaMut2 ΔΔG -0.81 kcal/mol (destabilising). A bilayer-embedded variant with a TM6-TM11 cross-helix mechanism.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | C505Y (p.Cysteine505Tyrosine) |
| **DNA change** | c.1514G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000918063 |
| **Amino acid change** | Cysteine (C) → Tyrosine (Y) — a small thiol-bearing residue replaced by a large aromatic ring carrying a hydroxyl group. Loss of disulfide-bond capacity and a substantial volume increase, plus introduction of an H-bond donor/acceptor inside a hydrophobic membrane. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 505** | **82.44** — well-folded |
| **Domain** | TM6 (496-516), helical transmembrane |
| **Position context** | TM6 (residues 496–516) · position 505 is bilayer-embedded. The hydrophobic membrane core penalizes the introduced tyrosine hydroxyl, which prefers polar or aqueous environments. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 496-516 Helical

> Position 505 sits inside TM6, one of wolframin's eleven transmembrane helices. The AlphaFold model places C505 within 5 Å of PRO504 (2.5 Å), LEU506 (2.5 Å), SER502 (3.6 Å), PRO885 (4.1 Å), VAL503 (4.2 Å), and TYR508 (4.3 Å). The most structurally significant neighbor is PRO885 — that's a residue from TM11 (Atlas card P885L adjacent), positioned 4.1 Å away in the AlphaFold structure. This contact indicates that TM6 and TM11 cross each other in the membrane and pack against one another through the C505/P885 region.

The wild-type cysteine at position 505 is small and hydrophobic-character — its thiol can either remain free or, in oxidizing conditions, participate in disulfide formation. The local environment here is bilayer-embedded so disulfide formation is not the dominant mechanism. The wild-type's small volume fits cleanly into the TM6-TM11 packing interface.

Replacing cysteine with tyrosine here is unusually disruptive for two reasons. First, the volume increase: tyrosine's aromatic ring is roughly four times the side-chain mass of cysteine. The TM6-TM11 interface, which packs tightly through the C505/P885 region, cannot accommodate the larger side chain without significant rearrangement. Second, the introduced hydroxyl is unfavorable in the bilayer hydrophobic core — it would prefer to point toward the membrane-water interface, dragging the local geometry with it.

DynaMut2's |ΔΔG| of 0.81 kcal/mol captures the modest energetic cost of the fold absorbing this rearrangement. But the functional consequence — disrupted TM6-TM11 packing — is more severe than the ΔΔG alone suggests. AlphaMissense's 0.892 score reflects this. Compare with P504L (Atlas card adjacent): proline at position 504 plays a deliberate helix-kinking role, and removing it has its own structural cost. The two variants together — C505Y and P504L — characterize a vulnerable region in TM6 where multiple substitutions produce convergent functional disruption.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8918** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.81 (Destabilising)** |
| Job ID | 177990265119 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990265119 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 1/01/01 00:00 |
| Inheritance | Documented in association with diabetes mellitus. The conservative substitution chemistry and bilayer location suggest the AD-leaning (Wolfram-like, DFNA6) presentation pattern. |
| WFS1 variant landscape | C505Y is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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| = 0.81 kcal/mol — fold survives. AlphaMissense 0.892 confirms deeply pathogenic signal.<br/><br/>The mechanism is disrupted TM6-TM11 helix-helix packing through the C505-P885 contact (4.1 Å in the AlphaFold model). The atlas-surfaced cross-helix interaction makes the therapeutic target geometric: a small molecule that stabilizes the TM6-TM11 interface, occupying the steric niche the wild-type cysteine maintained, would compensate.<br/><br/>The reciprocal Atlas card (P885L) shows the same interface from the TM11 side. Drug discovery targeting this interface has two converging mechanisms it could rescue simultaneously.

**Why this card matters.** C505Y is one of the Atlas's clearest examples of cross-helix contact variants. The pathogenic mechanism is invisible without the AlphaFold-derived neighbor analysis: pre-atlas, C505 looked like a TM6 problem; with the atlas, it's a TM6-TM11 interface problem with a known reciprocal variant (P885L). Drug design at this interface gets reinforced from both sides.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `C505Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 505 with ball-and-stick + neighbors within 5Å)
- `C505Y_variant_card.md` — this card (source of truth)
- `C505Y_variant_card.html` — styled printable card
- `C505Y_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)
- `C505Y_wildtype_interactions.pse` / `C505Y_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.*