D367G

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Aspartic acid → Glycine at position 367 · Lumenal loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type D367 — ionic bond to H401

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DynaMut2 mutant · D367G

Mutant G367 — ionic bond to H401 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	H401	—	Lost
Hydrogen bond	K363	K363	Preserved
Hydrogen bond	V364	—	Lost
Hydrogen bond	A370	A370	Preserved
Hydrogen bond	W371	W371	Preserved
Hydrogen bond	P404	—	Lost
Polar contact	K363	K363	Preserved
Polar contact	V364	V364	Preserved
Polar contact	A370	A370	Preserved
Polar contact	W371	W371	Preserved
Carbonyl	A370	—	Lost
Van der Waals	K363	—	Lost

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

0.14kcal/mol

Stabilising — mild

AlphaMissense

0.535

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsCataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome; Inborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.0010%

cDNA changec.1100A>G

ClinVar accessionVCV001315666

Last evaluated2025/06/16 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — D367G Variant Card

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

Aspartic acid → Glycine at position 367. Lumenal loop 1. ClinVar Uncertain significance, AlphaMissense 0.535, DynaMut2 ΔΔG +0.14 kcal/mol (stabilising).

Identity

Field	Value
Variant	D367G (p.Aspartic acid367Glycine)
DNA change	c.1100A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001315666
Amino acid change	Aspartic acid (D) → Glycine (G)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 367	79.50 — well-folded
Domain	Lumenal loop 1
Position context	C-terminal lumenal domain · position 367 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 367 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is negatively charged (aspartate — carboxylate); the mutant is small/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5353
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.14 (Stabilising)
Job ID	178094722672
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094722672

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/06/16 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	D367G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Cataract 41
Wolfram syndrome 1
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
Wolfram-like syndrome
Inborn genetic diseases

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.14 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.14 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.535. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
D367G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 367 with ball-and-stick + neighbors within 5Å)
D367G_variant_card.md — this card (source of truth)
D367G_variant_card.html — styled printable card
D367G_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)
D367G_wildtype_interactions.pse / D367G_mutant_interactions.pse — PyMOL sessions

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

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D367G PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download D367G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.