A465G

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

Alanine → Glycine at position 465 · Transmembrane helix 6 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A465 — hydrogen bond to T461

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DynaMut2 mutant · A465G

Mutant G465 — hydrogen bond to E462 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T461	T461	Preserved
Hydrogen bond	E462	E462	Preserved
Hydrogen bond	L468	L468	Preserved
Hydrogen bond	S469	S469	Preserved
Polar contact	T461	T461	Preserved
Polar contact	E462	E462	Preserved
Polar contact	L468	L468	Preserved
Polar contact	S469	S469	Preserved
Van der Waals	T461	—	Lost
Van der Waals	E462	—	Lost
Hydrophobic	L507	—	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

-1.38kcal/mol

Destabilising — moderate

AlphaMissense

0.439

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1394C>G

ClinVar accessionVCV002809219

Last evaluated2022/10/21 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A465G Variant Card

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

Alanine → Glycine at position 465. Transmembrane helix 6. ClinVar Uncertain significance, AlphaMissense 0.439, DynaMut2 ΔΔG -1.38 kcal/mol (destabilising).

Identity

Field	Value
Variant	A465G (p.Alanine465Glycine)
DNA change	c.1394C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002809219
Amino acid change	Alanine (A) → Glycine (G)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 465	81.38 — well-folded
Domain	Transmembrane helix 6
Position context	Inside Transmembrane helix 6 · position 465 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 465 sits in a transmembrane helix (Transmembrane helix 6). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); 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	0.4391
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.38 (Destabilising)
Job ID	178094702129
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094702129

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/10/21 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A465G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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|=1.38 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.38 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.439. 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
A465G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 465 with ball-and-stick + neighbors within 5Å)
A465G_variant_card.md — this card (source of truth)
A465G_variant_card.html — styled printable card
A465G_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)
A465G_wildtype_interactions.pse / A465G_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 A465G 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 A465G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.