# WFS1 Wolframin — Y669H Variant Card

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

*Tyrosine → Histidine at position 669 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic (stronger tier than the Y669C variant at the same position). AlphaMissense 0.997, DynaMut2 ΔΔG -1.20 kcal/mol (destabilising). A direct structural comparator to Y669C.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Y669H (p.Tyrosine669Histidine) |
| **DNA change** | c.2005T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001458745 |
| **Amino acid change** | Tyrosine (Y) → Histidine (H) — a large aromatic phenol replaced by a smaller titratable imidazole ring. Aromatic character partially preserved; pKa near physiological pH means the residue can be neutral or positively charged depending on local environment. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 669** | **87.75** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 669 in the ER lumen, well-folded region (pLDDT 88). Same structural environment as Y669C. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 669-669 in WFS1; dbSNP:rs1402999203
  - Natural variant: 669-669 in DFNA6

> Position 669 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places Y669 within 5 Å of GLN668 (2.5 Å), GLY670 (2.5 Å), TRP666 (3.8 Å), THR665 (4.0 Å), ALA671 (4.4 Å), and GLN667 (4.5 Å). The wild-type tyrosine ring makes edge-face π–π stacking with TRP666 and hydrogen-bonding contacts to nearby polar residues through its hydroxyl.

Replacing tyrosine with histidine here preserves more structural character than the cysteine substitution at the same position (Y669C, Atlas card adjacent). The imidazole ring of histidine is aromatic, so some π-stacking interaction with TRP666 is preserved — although the histidine imidazole is smaller, lacks the phenol's hydroxyl arm, and presents a different electrostatic surface. Critically, histidine's pKa is close to physiological pH; the residue can be neutral or positively charged depending on its local environment. The ER lumen is mildly acidic, which favors the protonated, charged form.

This substitution carries a larger DynaMut2 |ΔΔG| (1.20 kcal/mol) than Y669C (0.41 kcal/mol). Two factors explain the difference. First, histidine's larger volume creates steric mismatch where the tyrosine's hydroxyl arm previously projected into the local environment without conflict. Second, the introduced positive charge — when histidine is protonated in the mildly acidic ER lumen — destabilizes the local electrostatic context that the neutral tyrosine occupied. The net effect is a moderate but real destabilization of the local fold, while still leaving the protein fold globally intact.

The pathogenic classification ("Pathogenic" rather than the "Likely Pathogenic" of Y669C) reflects accumulated clinical evidence — multiple submitters, multiple cases — that this specific substitution has reliable functional consequences.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9972** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.2 (Destabilising)** |
| Job ID | 177990252046 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990252046 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2021/02/11 00:00 |
| Inheritance | Inheritance pattern not specified in this ClinVar entry. The stronger ClinVar tier reflects more accumulated evidence of pathogenicity than Y669C, but the mechanism and inheritance pattern likely overlap with Y669's role in the lumenal fold. |
| WFS1 variant landscape | Y669H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for Y669H — ClinVar Pathogenic classification established 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 1.20 kcal/mol — modest destabilization, fold intact. AlphaMissense 0.997 confirms severe functional consequence.<br/><br/>The mechanism is partly preserved aromatic stacking with TRP666 (the histidine imidazole is still aromatic) plus a new pH-dependent positive charge in a polar lumenal context. The therapeutic strategy is site-directed: a small molecule that occupies the steric niche the wild-type tyrosine ring occupied, ideally with the same H-bond donor capacity that the lost hydroxyl provided.<br/><br/>The two-variant comparison at position 669 (Y669H vs Y669C) is a clean teaching example of how substitution chemistry — not just position — drives severity and mechanism. The Atlas captures this resolution; pre-atlas drug discovery would not have.

**Why this card matters.** Y669 sits at a position where wolframin's lumenal fold packs aromatically against TRP666. Multiple ClinVar substitutions at this position (Y669C, Y669H) are pathogenic with different mechanisms and different severity. This is precisely the variant geometry that responds best to structure-based drug design: same local pocket, same therapeutic target, multiple variant chemistries requiring slight design variations.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Y669H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 669 with ball-and-stick + neighbors within 5Å)
- `Y669H_variant_card.md` — this card (source of truth)
- `Y669H_variant_card.html` — styled printable card
- `Y669H_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)
- `Y669H_wildtype_interactions.pse` / `Y669H_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.*