# WFS1 Wolframin — G674V Variant Card

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

*Glycine → Valine at position 674 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, monogenic hearing loss. AlphaMissense 0.983, DynaMut2 ΔΔG -0.24 kcal/mol (destabilising). The FOURTH pathogenic substitution catalogued at position 674 in the Atlas — with G674E, G674R, G674W.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G674V (p.Glycine674Valine) |
| **DNA change** | c.2021G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV004685574 |
| **Amino acid change** | Glycine (G) → Valine (V) — smallest amino acid replaced by branched hydrophobic. Loss of backbone flexibility; modest volume increase. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 674** | **84.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 674 in the ER lumen (pLDDT 84). Same environment as the rest of the G674 series. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 674-674 in dbSNP:rs200672755

> Position 674 sits in wolframin's C-terminal lumenal domain. Same neighbor environment as the G674E/R/W series: CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), ARG676 (4.5 Å).

Replacing glycine with valine removes the wild-type backbone flexibility but introduces a more conservative side chain than G674E/R/W. The branched aliphatic valine fits the local environment better than charged or bulky alternatives — the |ΔΔG| of 0.24 is the smallest of the G674 series.

Yet AlphaMissense's 0.983 plus monogenic hearing loss clinical evidence confirm severe functional consequence. The mechanism is still loss of glycine's structural flexibility role, even though the variant residue's chemistry is conservative.

G674V is the most chemically conservative substitution at position 674 — and the smallest |ΔΔG| in the series — yet still pathogenic. This confirms the Atlas's hypothesis that the wild-type glycine at this position is structurally irreplaceable regardless of which residue substitutes.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9834** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.24 (Destabilising)** |
| Job ID | 177991928699 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991928699 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/11/18 00:00 |
| Inheritance | Monogenic hearing loss documented. |
| WFS1 variant landscape | G674V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.24 kcal/mol — fold survives. AlphaMissense 0.983 + monogenic hearing loss confirm severe functional consequence.<br/><br/>The mechanism is loss of glycine flexibility at position 674. Therapeutic strategy: same target as G674E/R/W — restore the wild-type backbone geometry at the C673-G674-P675 microregion.

**Why this card matters.** G674V completes the FOUR-substitution series at position 674. Across these variants, the same therapeutic target geometry rescues all of them. The Atlas establishes position 674 as one of the highest-value druggability hotspots in WFS1.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G674V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 674 with ball-and-stick + neighbors within 5Å)
- `G674V_variant_card.md` — this card (source of truth)
- `G674V_variant_card.html` — styled printable card
- `G674V_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)
- `G674V_wildtype_interactions.pse` / `G674V_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.*