# WFS1 Wolframin — A684T Variant Card

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

*Alanine → Threonine at position 684 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.952, DynaMut2 ΔΔG +0.11 kcal/mol — essentially neutral (slightly stabilising). A polar-introduction variant adjacent to the R685 position (R685P atlas card).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A684T (p.Alanine684Threonine) |
| **DNA change** | c.2050G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001458816 |
| **Amino acid change** | Alanine (A) → Threonine (T) — a small hydrophobic methyl-bearing residue replaced by a small polar hydroxyl-bearing residue. The substitution adds H-bond donor/acceptor capacity at a position that previously had none. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 684** | **87.94** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 684 in the ER lumen (pLDDT 88). Immediately adjacent to R685 in sequence. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 684-684 in WFSL; greatly reduces protein expression compared to wild-type; dbSNP:rs387906930

> Position 684 sits in wolframin's C-terminal lumenal domain, immediately preceding R685. The AlphaFold model places A684 within 5 Å of MET683 (2.5 Å), ARG685 (2.5 Å — the partner residue in R685P atlas card), GLN687 (4.0 Å), ASN682 (4.0 Å), and THR686 (4.4 Å). The local environment is heavy on polar and basic residues (R685, Q687, N682, T686).

The wild-type alanine at 684 provides minimal side-chain volume and no functional groups — it serves as a steric placeholder between M683 and R685. Replacing it with threonine introduces a polar hydroxyl group into a polar-rich environment. The hydroxyl could either form a new hydrogen bond with R685, T686, N682, or Q687, or perturb the existing H-bond network among those residues.

The ΔΔG of +0.11 indicates near-neutral structural impact — the new H-bonding option roughly compensates for any local strain. But AlphaMissense's 0.952 score plus the ClinVar Pathogenic classification confirm pathogenic mechanism.

The mechanism is most plausibly disruption of the R685 H-bond network. The wild-type A684 placeholder allows R685 to project its side chain in a specific direction; the introduced T684 hydroxyl competes for R685's H-bonding attention and pulls it out of its functional orientation. Combined with the R685P atlas card (same R685 environment disrupted from the other side), this microregion has two convergent therapeutic targets.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9523** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.11 (Stabilising)** |
| Job ID | 177990264347 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990264347 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/10/15 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic. |
| WFS1 variant landscape | A684T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for A684T — 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 3/4 — Most Druggable**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.11 kcal/mol — essentially no fold change. AlphaMissense 0.952 confirms pathogenic functional consequence.<br/><br/>The mechanism is introduction of a new H-bond donor that captures or redirects R685's functional H-bonding, disrupting the partner-recognition surface R685 normally provides. Drug discovery targets the R685 microregion — same target as R685P, approached from a different angle.<br/><br/>Two Atlas variants in the same 683-687 region converge on a single therapeutic geometry: a small molecule that stabilizes the wild-type R685 orientation.

**Why this card matters.** A684T pairs with R685P in the Atlas as sister variants at adjacent positions, both disrupting the same R685 partner-recognition geometry. The two are pedagogically important: they show that pathogenic variants don't have to be at the same position to share a therapeutic target — adjacent positions with overlapping structural roles produce the same drug-discovery opportunity.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A684T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 684 with ball-and-stick + neighbors within 5Å)
- `A684T_variant_card.md` — this card (source of truth)
- `A684T_variant_card.html` — styled printable card
- `A684T_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)
- `A684T_wildtype_interactions.pse` / `A684T_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.*