# WFS1 Wolframin — A806P Variant Card

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

*Proline substitution in a tightly packed C-terminal lumenal segment — backbone rigidity is introduced where the protein needs torsional freedom, and the ATF6-interacting sensor face takes the hit.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | A806P (p.Alanine806Proline) |
| **DNA change** | c.2416G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001073764 |
| **Amino acid change** | Alanine (small, hydrophobic, unrestricted backbone phi/psi) to Proline (cyclic side chain, locks phi near -60 degrees, eliminates the backbone amide NH as a hydrogen-bond donor) at position 806. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 806** | **90.88** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | Position 806 sits deep in wolframin's largest soluble module — the C-terminal lumenal domain (residues 653-869) that faces the ER lumen and houses the ATF6-binding interface, the Na+/K+ ATPase beta1 contact, and the calcium-sensing apparatus. pLDDT 90.88 places the residue inside a confidently modeled, well-ordered region. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> A806 occupies a tightly packed region of the lumenal domain, framed by Ser807 (2.42 Angstrom), Arg805 (2.44 Angstrom), and an aromatic shell drawn in by Phe775 (3.82 Angstrom), Phe810 (4.09 Angstrom), and the aliphatic Leu842 (4.22 Angstrom) and Leu804 (4.82 Angstrom). The wild-type alanine's compact methyl side chain is tolerated here precisely because it does not perturb the backbone, leaving the phi/psi angles free to accommodate the local turn geometry that brings the Phe775-Phe810 aromatic pair into close register with the Arg805 guanidinium just one residue away.

Proline destroys that arrangement. Its pyrrolidine ring forces backbone phi near -60 degrees and eliminates the amide NH, which means the residue can no longer donate a hydrogen bond to upstream carbonyls and can no longer adopt the phi angle the wild-type loop requires. In a transmembrane helix this would break the helix outright; in this lumenal segment, the cost is a forced kink and the displacement of the immediately adjacent Arg805 — the polar/charged anchor that almost certainly contributes to the lumenal hydrogen-bond network around the ATF6-sensing face.

DynaMut2 reports DeltaDeltaG = +0.7 kcal/mol (labelled stabilising by the local energy function, which over-weights van der Waals packing gains from proline's rigid ring). The interpretation here is not that the fold is more stable globally — it is that the residue's new conformation is locally favorable while the protein's downstream geometry is forced off its native trajectory. AlphaMissense scores this 0.991 — about as high a pathogenicity score as the model produces, indicating that despite the mild DeltaDeltaG, the evolutionary signal at this position is unambiguous: A806 is conserved for a reason the energy function alone cannot see.

The Phe775-Phe810 aromatic contact within 4 Angstrom of A806 is the structural detail most likely affected. Two phenylalanines stacked at this distance constitute a pi-stacking interaction worth 2-4 kcal/mol on their own, and the proline-induced backbone kink almost certainly displaces one or both rings out of register. Combined with the loss of the Arg805 anchor, the consequence is a localized rearrangement of the ATF6-sensing face — a high-leverage mechanistic story that the gross stability number does not tell.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9912** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.7 (Stabilising)** |
| Job ID | 177991404561 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991404561 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2023/07/31 00:00 |
| Inheritance | Autosomal dominant and autosomal recessive forms both reported. |
| WFS1 variant landscape | A806P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- WFS1-Related Spectrum Disorders

---

## 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**

Final classification: Category 4 — Stable Fold, Function Disrupted. The convergent evidence reads cleanly: pLDDT 90.88 places A806 inside an ordered, modelable region (no IDR exclusion); DeltaDeltaG magnitude of 0.7 kcal/mol means the fold survives the substitution — this is not gross misfolding requiring gene replacement; AlphaMissense 0.991 confirms the position is functionally constrained despite mild energetic cost; and the lumenal location places the perturbation directly on the ATF6-sensing face, the most therapeutically interesting surface in wolframin.

The lost contact set is specific and small. A pharmacological chaperone or site-directed small molecule that restores the Phe775-Phe810 aromatic register, or that compensates for the Arg805 displacement, becomes the obvious next experiment. The fold is intact; the lesion is local; the surface is accessible from the lumen. Gene therapy is not warranted at this magnitude — this is exactly the bucket where the Atlas thesis predicts small-molecule rescue should outperform AAV.

**Why this card matters.** A806P is one of the cleanest illustrations of why DeltaDeltaG alone is not enough. A naive read of the stability number (mildly stabilising) would put this variant in a low-priority bin; the AlphaMissense score and the structural specifics tell the opposite story. The Atlas's value here is precisely that it forces the reader to look at the residue's neighbors, the backbone constraint, and the functional surface — not just the energy.

For the wolframin program, A806P is a candidate proof point for the pharmacological-chaperone hypothesis. If a CFTR-corrector-style molecule can stabilize the native lumenal geometry around the Phe775-Phe810 stack, the same chemistry should transfer to other lumenal Category 4 variants in this neighborhood. That makes A806P a structural anchor for downstream screening work, not just a single clinical case.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A806P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 806 with ball-and-stick + neighbors within 5Å)
- `A806P_variant_card.md` — this card (source of truth)
- `A806P_variant_card.html` — styled printable card
- `A806P_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)
- `A806P_wildtype_interactions.pse` / `A806P_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*