# WFS1 Wolframin — K634T Variant Card

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

*Lysine → Threonine at position 634 inside wolframin's tenth transmembrane helix (TM10). ClinVar Pathogenic, associated with DFNA6 hearing loss. AlphaMissense 0.883, DynaMut2 ΔΔG -0.32 kcal/mol (destabilising). A charge-loss variant in a TM helix.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K634T (p.Lysine634Threonine) |
| **DNA change** | c.1901A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000004524 |
| **Amino acid change** | Lysine (K) → Threonine (T) — large positively-charged primary amine replaced by small polar hydroxyl. Both can hydrogen-bond, but charge is lost and side-chain length is dramatically reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 634** | **82.69** — well-folded |
| **Domain** | TM10 (632-652), helical transmembrane |
| **Position context** | TM10 (residues 632–652) · position 634 is at the very start of TM10, in the membrane interface region (pLDDT 83). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 632-652 Helical
  - Natural variant: 634-634 in DFNA6; dbSNP:rs104893882

> Position 634 sits at the start of TM10. The AlphaFold model places K634 within 5 Å of LEU635 (2.5 Å), VAL633 (2.5 Å), SER631 (3.8 Å), SER630 (4.0 Å), and MET632 (4.3 Å). The local environment is hydrophobic-rich with two nearby serines (S630, S631) — characteristic of a TM-helix start in the lipid headgroup region.

The wild-type lysine at 634 is positioned where its long alkyl chain can extend toward the membrane-water interface and its primary amine can engage phospholipid headgroups. This is a 'positive-inside rule' position — basic residues at the cytoplasmic end of TM helices are stabilizing for membrane orientation.

Replacing lysine with threonine removes this positive-inside anchor. The new T634 is small and polar but cannot reach the membrane interface or engage headgroups. TM10's orientation may shift slightly to compensate.

The |ΔΔG| of 0.32 reflects modest structural cost. AlphaMissense's 0.883 score plus the DFNA6 clinical association confirm pathogenic consequence — likely from altered TM10 topology and downstream effects on helix-helix packing (notably the TM3-TM10 interface that T641K disrupts).

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8832** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.32 (Destabilising)** |
| Job ID | 177990265685 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990265685 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | no assertion criteria provided |
| Last evaluated | 2002/01/01 00:00 |
| Inheritance | Autosomal dominant DFNA6 hearing loss documented. |
| WFS1 variant landscape | K634T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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| = 0.32 kcal/mol — fold survives. AlphaMissense 0.883 + DFNA6 clinical association confirm pathogenic functional consequence.<br/><br/>The mechanism is loss of the positive-inside anchor at the TM10 cytoplasmic end, with secondary effect on TM10's overall topology and TM3-TM10 packing. Therapeutic strategy: site-directed at the TM10 N-terminal membrane interface.<br/><br/>Combined with T641K (Atlas card adjacent — TM10 mid-helix with TM3-TM10 interface mechanism), drug discovery targeting TM10 has two convergent variant targets.

**Why this card matters.** K634T illustrates the 'positive-inside rule' in WFS1 — basic residues at TM helix termini are deliberate anchors. Their loss perturbs membrane topology even when overall fold survives. The Atlas captures this through the neighbor analysis at the cytoplasmic end of TM10.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K634T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 634 with ball-and-stick + neighbors within 5Å)
- `K634T_variant_card.md` — this card (source of truth)
- `K634T_variant_card.html` — styled printable card
- `K634T_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)
- `K634T_wildtype_interactions.pse` / `K634T_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.*