# WFS1 Wolframin — A31G Variant Card

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

*Alanine → Glycine at position 31 in wolframin's N-terminal intrinsically disordered region (IDR). ClinVar carries conflicting classifications. AlphaMissense 0.100 (likely BENIGN). pLDDT 28 — deep IDR. DynaMut2 ΔΔG -0.35 kcal/mol but NOT trustworthy. A Category 5 IDR variant flagged for wet-lab validation.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A31G (p.Alanine31Glycine) |
| **DNA change** | c.92C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215373 |
| **Amino acid change** | Alanine (A) → Glycine (G) — a small hydrophobic methyl-bearing residue replaced by the smallest amino acid (no side chain). The substitution removes a methyl group and adds backbone flexibility. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 31** | **28.33** — **IDR (below 50 threshold)** |
| **Domain** | N-terminal intrinsically disordered region (1-86) |
| **Position context** | N-terminal intrinsically disordered region (residues 1–86) · position 31 sits in a region with pLDDT 28, deep in IDR territory. The AlphaFold model is not predictive here. |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Region: 1-86 Disordered

> Position 31 sits in wolframin's N-terminal IDR. The pLDDT score of 28 indicates that AlphaFold cannot reliably predict the local conformation — the protein adopts an ensemble of structures in this region rather than a single fold. Neighbor analysis returns only the immediate sequence neighbors (SER32 at 2.5 Å, THR30 at 2.6 Å, LEU33 at 4.6 Å) — the structural signature of IDR.

Replacing alanine with glycine adds backbone flexibility. Glycine permits backbone conformations (especially in the Ramachandran left-handed helix region) that other amino acids cannot adopt. In a folded protein this is sometimes structurally significant. In an IDR, where the protein is already conformationally heterogeneous, the impact is more subtle — the ensemble's accessible conformational space shifts slightly, but no single 'wild-type' geometry is being broken.

DynaMut2's |ΔΔG| of 0.35 kcal/mol is not interpretable as a quantitative claim in this region. AlphaMissense's 0.100 score (well below the 0.564 pathogenic threshold) considers the variant likely benign.

The conflicting ClinVar classifications — some pathogenic, some uncertain — likely reflect that this variant has been observed in patients with Wolfram-spectrum disease but causal contribution has not been firmly established. The mechanism, if pathogenic, would likely involve IDR-mediated phase separation, partner binding through disordered regions, or context-dependent functional disruption — none of which AlphaMissense's training reliably captures.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0998** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.35 (Destabilising)** |
| Job ID | 177992520829 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992520829 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/10 00:00 |
| Inheritance | Inheritance pattern uncertain given conflicting ClinVar classifications. Documented in patients with Wolfram syndrome and inborn genetic diseases. |
| WFS1 variant landscape | A31G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Inborn genetic diseases
- 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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion.</strong> pLDDT = 28 places this variant deep in wolframin's IDR. DynaMut2 stability predictions are not trustworthy here. AlphaMissense's score of 0.100 (likely benign) raises a substantive question about whether the variant is genuinely pathogenic or is a benign variant observed by association.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery. For A31G specifically, the recommended next steps are: (1) verify the clinical association with case-by-case review; (2) characterize the IDR's functional role; (3) test the variant in functional assays. Therapeutic strategy decisions should not be made on the current computational data alone.

**Why this card matters.** A31G is one of two IDR-pair Category 5 variants in this batch (with G78R). Both sit in wolframin's N-terminal disordered region, both have AlphaMissense scores in the likely-benign range, both carry conflicting ClinVar classifications. The Atlas appropriately flags these as exclusions from the computational drug discovery pipeline. Pre-atlas analysis might have included them as therapeutic targets; the Atlas's IDR-exclusion logic is what prevents that misallocation of effort.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A31G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 31 with ball-and-stick + neighbors within 5Å)
- `A31G_variant_card.md` — this card (source of truth)
- `A31G_variant_card.html` — styled printable card
- `A31G_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)
- `A31G_wildtype_interactions.pse` / `A31G_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.*