# WFS1 Wolframin — Y650H Variant Card

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

*Tyrosine → Histidine at position 650 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic. AlphaMissense 0.518 (AMBIGUOUS — at the likely-pathogenic threshold), DynaMut2 ΔΔG +0.05 kcal/mol (essentially neutral). pLDDT 69 — borderline confidence. A variant in a confidence-edge region with ambiguous AM signal but confirmed clinical pathogenicity.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Y650H (p.Tyrosine650Histidine) |
| **DNA change** | c.1948T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002203525 |
| **Amino acid change** | Tyrosine (Y) → Histidine (H) — aromatic phenol replaced by aromatic imidazole. Both are aromatic and titratable; histidine is smaller and its imidazole has different pKa than tyrosine's phenol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 650** | **68.69** — confident |
| **Domain** | TM10 (632-652), helical transmembrane |
| **Position context** | TM10 (residues 632–652) · position 650 is near the C-terminus of TM10, approaching the membrane-lumen interface. pLDDT 69 indicates borderline AlphaFold confidence. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 632-652 Helical

> Position 650 sits near the end of TM10. The AlphaFold model places Y650 within 5 Å of PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å), PHE646 (3.7 Å), and TRP648 (4.4 Å). The local environment is dominated by aromatic residues (F649, F646, W648) plus a cysteine (C647) — a tightly-packed aromatic cluster at the end of TM10.

The wild-type tyrosine ring participates in π-stacking with the surrounding aromatic residues (F649, F646, W648). The hydroxyl can H-bond to C647's backbone or to a nearby polar residue. The local environment is densely aromatic — a structural feature that requires precise geometric matching.

Replacing tyrosine with histidine preserves some aromatic character (histidine's imidazole is aromatic) but the geometry shifts substantially. Histidine's imidazole is smaller and oriented differently than tyrosine's phenol. The π-stacking pattern with F649/F646/W648 reorganizes.

The DynaMut2 ΔΔG of essentially zero (+0.05) indicates fold accommodates the swap easily — both residues fit in the local pocket. But AlphaMissense's 0.518 is borderline (just below the 0.564 likely-pathogenic threshold), and ClinVar Pathogenic + the borderline pLDDT (69) together create an ambiguous interpretation.

The variant is likely pathogenic by a specific mechanism (disrupted aromatic stacking geometry in the TM10 C-terminal aromatic cluster) but the AM signal is weak. This is a variant where wet-lab characterization would be especially valuable.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5180** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.05 (Stabilising)** |
| Job ID | 177990266996 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990266996 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/03/09 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | Y650H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for Y650H — 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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted (borderline confidence).</strong> ΔΔG = +0.05 kcal/mol — fold essentially unchanged. AlphaMissense 0.518 is at the boundary of likely-pathogenic. pLDDT 69 borderline. ClinVar Pathogenic confirms clinical relevance.<br/><br/>The mechanism is reorganization of an aromatic stacking cluster (F646, F649, W648) at the C-terminal end of TM10. Therapeutic strategy: site-directed at the TM10 aromatic cluster. Wet-lab characterization is strongly recommended before therapeutic strategy is finalized given the AM and pLDDT borderline signals.

**Why this card matters.** Y650H is a 'gray zone' variant — pathogenic by ClinVar but with borderline AlphaMissense score and borderline AlphaFold confidence. The Atlas surfaces this complexity rather than papering over it. Drug discovery here should pause for wet-lab validation rather than committing to a computational-only design strategy.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Y650H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 650 with ball-and-stick + neighbors within 5Å)
- `Y650H_variant_card.md` — this card (source of truth)
- `Y650H_variant_card.html` — styled printable card
- `Y650H_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)
- `Y650H_wildtype_interactions.pse` / `Y650H_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.*