# WFS1 Wolframin — P292S Variant Card

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

*Proline → Serine at position 292 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic for classical Wolfram syndrome 1. AlphaMissense 0.957, DynaMut2 ΔΔG -0.74 kcal/mol (destabilising). Critically, pLDDT at this position is 54 — just above the Category 5 IDR threshold but in a low-confidence region.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P292S (p.Proline292Serine) |
| **DNA change** | c.874C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003377398 |
| **Amino acid change** | Proline (P) → Serine (S) — a rigid, helix-breaking residue replaced by a small polar hydroxyl-bearing residue. The substitution removes the proline's backbone constraint and introduces hydrogen-bonding capacity. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 292** | **54.16** — confident |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 292 sits in a region with relatively low AlphaFold confidence (pLDDT 54), just above the Cat 5 IDR threshold of 50. Interpret structural predictions here with caution. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Natural variant: 292-292 in WFS1; dbSNP:rs746923441

> Position 292 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places P292 within 5 Å of LEU293 (2.5 Å), TYR291 (2.5 Å), VAL288 (3.6 Å), HIS294 (4.4 Å), and ALA295 (4.7 Å). The local environment is mixed hydrophobic-polar.

The wild-type proline at 292 likely plays a deliberate structural role — proline residues in cytoplasmic domains often define loop boundaries or contribute backbone constraints that orient the domain for partner binding. Replacing it with serine removes that backbone constraint and adds a hydroxyl group with H-bond capacity.

The |ΔΔG| of 0.74 kcal/mol is interpretively complicated by the pLDDT of 54. DynaMut2 assumes a meaningful input structure; at pLDDT 54 the local AlphaFold prediction has lower confidence than the typical Atlas variant. The ΔΔG should be read as a directional indicator rather than a quantitative claim. AlphaMissense's 0.957 score is independently supportive — the substitution is pathogenic even if the structural mechanism is partially obscured by model uncertainty.

ClinVar Likely Pathogenic for classical Wolfram syndrome 1 confirms the variant's clinical relevance.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9567** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.74 (Destabilising)** |
| Job ID | 177991929544 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991929544 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2022/03/31 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented in ClinVar. |
| WFS1 variant landscape | P292S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 (with caveat).</strong> |ΔΔG| = 0.74 kcal/mol below the fold-integrity threshold. AlphaMissense 0.957 confirms pathogenic signal. However, pLDDT of 54 means the structural details deserve experimental validation before drug design proceeds.<br/><br/>The mechanism is removal of a deliberate proline backbone constraint plus introduction of a polar hydroxyl. Therapeutic strategy: a small molecule that stabilizes the wild-type backbone geometry around the position 292 loop region. Pharmacological chaperone screening is the safer initial approach given the structural confidence caveat.

**Why this card matters.** P292S sits in a borderline-confidence region of the AlphaFold model. The Atlas captures this with the pLDDT score; pre-atlas drug discovery would have either treated the variant at full structural confidence (overconfident) or ignored it entirely (under-utilizing the AlphaMissense signal). The dual-metric framing makes the appropriate caution visible — proceed with chaperone screening, validate experimentally, then proceed to docking once the structural geometry is confirmed.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P292S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 292 with ball-and-stick + neighbors within 5Å)
- `P292S_variant_card.md` — this card (source of truth)
- `P292S_variant_card.html` — styled printable card
- `P292S_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)
- `P292S_wildtype_interactions.pse` / `P292S_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.*