# WFS1 Wolframin — G736S Variant Card

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

*A glycine-to-serine substitution at a lumenal turn that brings a free thiol (Cys733) and a histidine (His766) into structural register — backbone freedom is lost where wolframin requires it, and the polar cluster reorganizes.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G736S (p.Glycine736Serine) |
| **DNA change** | c.2206G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001328696 |
| **Amino acid change** | Glycine (no side chain, uniquely permissive backbone freedom — the only amino acid that fits Ramachandran-disallowed phi/psi regions) to Serine (small polar hydroxyl, restricted to standard backbone geometry) at position 736. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 736** | **88.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | Position 736 sits in wolframin's C-terminal lumenal domain (residues 653-869) — the ATF6-interacting, Na+/K+ ATPase beta1-contacting, calcium-handling module. pLDDT 88.12 places G736 in an ordered, well-modeled environment. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 736-736 in WFS1; dbSNP:rs71532864

> G736 is wedged between Glu737 (2.41 Angstrom) and Tyr735 (2.47 Angstrom), with a through-space contact cluster reading Arg732 (3.07 Angstrom), His766 (3.29 Angstrom), Ile767 (4.09 Angstrom), Cys733 (4.88 Angstrom), and Leu734 (5.00 Angstrom). The local geometry is structurally complex: a tyrosine-glycine-glutamate sequence sandwiched between an arginine three residues upstream, a histidine six residues downstream by sequence but within 3.3 Angstrom by space, and a free cysteine within 5 Angstrom.

The wild-type glycine at 736 is doing exactly what glycines do best — providing the backbone flexibility that brings Arg732 (3.07 Angstrom), the Tyr735 phenol, and His766 (3.29 Angstrom) into close polar register. The Tyr735 hydroxyl, the Arg732 guanidinium, the Glu737 carboxylate, and the His766 imidazole are all polar-functional groups that the local geometry stages into a hydrogen-bond / electrostatic network. Glycine's job here is to allow the backbone turn that makes this network possible.

Replacing G736 with serine removes the disallowed-region phi/psi freedom and forces the chain into standard geometry. The Tyr735-Arg732-His766 register opens up; the Glu737 contact shifts; the local polar network — which is almost certainly part of the lumenal-domain functional surface — is degraded. DynaMut2's DeltaDeltaG of -1.1 kcal/mol captures the moderate destabilization; AlphaMissense at 0.862 confirms the position is evolutionarily constrained.

The Cys733 at 4.88 Angstrom is a secondary concern. In the wild-type configuration, the geometry holds Cys733 in a defined position relative to the polar cluster. The G736S-induced rearrangement may expose Cys733's thiol to a different local environment, potentially raising disulfide-formation risk in the oxidizing ER lumen. This is inference, not observation, but the structural signature supports it.

ClinVar links G736S to Wolfram syndrome 1, Wolfram-like syndrome, and monogenic hearing loss — phenotypic breadth consistent with partial loss of lumenal-domain function.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8624** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.1 (Destabilising)** |
| Job ID | 177991407335 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991407335 |

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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 | Both autosomal dominant and autosomal recessive forms documented. |
| WFS1 variant landscape | G736S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Wolfram-like syndrome
- Monogenic hearing loss

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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 88.12, DeltaDeltaG magnitude 1.1 kcal/mol, AlphaMissense 0.862, lumenal placement — the convergent profile sits inside the pharmacological-chaperone bucket. The lesion is a single backbone-freedom loss with downstream effects on a polar functional cluster (Arg732, Tyr735, His766, Glu737).

The drug design target is the multi-residue polar cluster, not G736 itself. A small molecule that engages the Arg732-Tyr735-His766 arrangement and restores the wild-type geometric register should compensate for the lost glycine flexibility. The Cys733 disulfide-formation risk should be modeled explicitly: any candidate compound should be tested for whether it stabilizes Cys733 in its reduced state.

**Why this card matters.** G736S is another representative of the lumenal glycine-loss cluster (alongside G702S, G695D, and others). The Atlas should treat these as a mechanistically unified set — same loss type (backbone freedom), same domain (lumenal), and likely overlapping chaperone-screening hits. If a single small molecule rescues two or three lumenal glycine-loss variants, the screening hit ratio for downstream development jumps substantially.

For the wolframin program, mapping the constellation of glycines in the lumenal domain is high-leverage atlas work. Each is potentially a Cat 3 variant; together they constitute a chemically tractable set with shared design logic.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G736S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 736 with ball-and-stick + neighbors within 5Å)
- `G736S_variant_card.md` — this card (source of truth)
- `G736S_variant_card.html` — styled printable card
- `G736S_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)
- `G736S_wildtype_interactions.pse` / `G736S_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.*