# WFS1 Wolframin — G702S Variant Card

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

*A conserved glycine inside a tight lumenal hairpin gives way to serine — the loss of glycine's torsional freedom is the entire mechanism, and the neighboring Arg703 hydrogen-bond partner is the structural casualty.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G702S (p.Glycine702Serine) |
| **DNA change** | c.2104G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001373337 |
| **Amino acid change** | Glycine (no side chain, uniquely permissive phi/psi geometry — the only amino acid that comfortably populates the disallowed Ramachandran region) to Serine (small polar hydroxyl, restricted to standard backbone angles) at position 702. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 702** | **88.75** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | Position 702 sits in wolframin's C-terminal lumenal domain (residues 653-869) — the ATF6-interacting, Na+/K+ ATPase beta1-contacting, calcium-sensing module that faces the ER lumen. pLDDT 88.75 places it inside a well-modeled region. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> G702 is wedged into a dense lumenal core. Its immediate covalent neighbors Arg703 (2.44 Angstrom) and Thr701 (2.45 Angstrom) flank it; the through-space contacts read like a packed hydrophobic-polar cluster — Val779 (3.50 Angstrom), Gly780 (3.54 Angstrom), Pro782 (3.76 Angstrom), Ile823 (3.89 Angstrom), Met781 (4.06 Angstrom), Phe825 (4.42 Angstrom). The Gly702-Gly780 pairing across 3.5 Angstrom is structurally interesting: two glycines in close apposition usually means a turn or hairpin that requires both backbones to adopt unusual phi/psi angles unavailable to other residues.

Replacing G702 with serine eliminates that geometric license. Serine has a beta-carbon and a hydroxyl, both compatible with standard Ramachandran space but incompatible with the disallowed-region phi/psi values that glycine populates here. The local backbone is forced to find a new conformation, and because Arg703 is the immediate downstream neighbor, the rearrangement carries Arg703's guanidinium with it — almost certainly displacing whatever salt bridge or hydrogen bond Arg703 contributes to the lumenal contact network with Pro782, Met781, or the Phe825 ring.

DynaMut2 returns DeltaDeltaG = -1.25 kcal/mol — destabilising and on the upper edge of the mild bucket. AlphaMissense 0.944 reads this as clearly pathogenic. The combination is consistent with a residue whose evolutionary indispensability is purely geometric: glycine is conserved at 702 not for any chemical contribution it makes but for the backbone freedom it provides. Any other residue, even one as conservative as serine, breaks the hairpin.

Clinically, G702S is documented in Wolfram syndrome 1 and optic atrophy — phenotypes that fit a lumenal-domain perturbation interfering with the ATF6 unfolded protein response axis. The fold survives; the function does not.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9436** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.25 (Destabilising)** |
| Job ID | 177991405251 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991405251 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2026/01/26 00:00 |
| Inheritance | Autosomal recessive (Wolfram syndrome 1 form documented in ClinVar). |
| WFS1 variant landscape | G702S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Optic atrophy

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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**

Final classification: Category 3 — Most Druggable. pLDDT 88.75 puts G702 in an ordered, modelable region; the DeltaDeltaG magnitude (1.25 kcal/mol) is firmly inside the small-molecule rescue window; AlphaMissense 0.944 confirms strong functional constraint; and the disrupted contact set — Arg703 and its through-space partners around Pro782/Met781/Phe825 — is small and spatially defined.

The therapeutic frame is a pharmacological chaperone that restores the hairpin geometry at the Gly702-Gly780 turn. CFTR-corrector-class molecules that bind misfolded membrane proteins and recover near-native geometry are the direct analogue. Importantly, the Atlas should treat the G702-G780 pair as a single targetable site: any compound that stabilizes the wild-type backbone arrangement at G702 likely also stabilizes G780 and the surrounding aromatic-aliphatic packing.

**Why this card matters.** Glycine-loss variants are a recurring motif in the Atlas because glycine carries information that no other residue can substitute for — pure backbone freedom. When a glycine is conserved, the protein needs precisely the disallowed phi/psi space it provides, and substitution is mechanistically equivalent to a torsional restraint. G702S exemplifies the class.

For wolframin specifically, position 702 sits in the same lumenal region as several other glycine-substitution variants documented in ClinVar. Mapping the constellation of glycine residues across the lumenal domain may identify a small set of hairpin sites that all share the same therapeutic logic: a single pharmacological chaperone could potentially rescue multiple Cat 3 glycine variants at once, which is precisely the kind of leverage the Atlas thesis predicts.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G702S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 702 with ball-and-stick + neighbors within 5Å)
- `G702S_variant_card.md` — this card (source of truth)
- `G702S_variant_card.html` — styled printable card
- `G702S_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)
- `G702S_wildtype_interactions.pse` / `G702S_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.*