A458T

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Alanine → Threonine at position 458 · Cytoplasmic loop 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A458 — hydrogen bond to Y454

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DynaMut2 mutant · A458T

Mutant T458 — hydrogen bond to T461 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost5 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y454	Y454	Preserved
Hydrogen bond	T461	T461	Preserved
Hydrogen bond	E462	E462	Preserved
Hydrogen bond	—	F515	Gained
Hydrogen bond	—	Y534	Gained
Polar contact	Y454	Y454	Preserved
Polar contact	T455	T455	Preserved
Polar contact	A460	—	Lost
Polar contact	T461	T461	Preserved
Polar contact	E462	E462	Preserved
Polar contact	—	L511	Gained
Polar contact	—	F515	Gained
Polar contact	Y534	Y534	Preserved
Van der Waals	Y454	—	Lost
Van der Waals	T461	—	Lost
Van der Waals	—	M518	Gained
Van der Waals	Y534	Y534	Preserved
Hydrophobic	L514	L514	Preserved
Hydrophobic	M518	M518	Preserved
Hydrophobic	Y534	Y534	Preserved

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

-1.81kcal/mol

Destabilising — moderate

AlphaMissense

0.674

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00066%

cDNA changec.1372G>A

ClinVar accessionVCV002149077

Last evaluated2024/10/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A458T Variant Card

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

Alanine → Threonine at position 458. Cytoplasmic loop 3. ClinVar Uncertain significance, AlphaMissense 0.674, DynaMut2 ΔΔG -1.81 kcal/mol (destabilising).

Identity

Field	Value
Variant	A458T (p.Alanine458Threonine)
DNA change	c.1372G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002149077
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 458	86.69 — well-folded
Domain	Cytoplasmic loop 3
Position context	Loop region · position 458 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 458 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6744
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.81 (Destabilising)
Job ID	178092127084
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092127084

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/10/15 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A458T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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><br/><br/>|ΔΔG|=1.81 < 2 kcal/mol (fold intact) + AlphaMissense 0.674 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.674. 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
A458T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 458 with ball-and-stick + neighbors within 5Å)
A458T_variant_card.md — this card (source of truth)
A458T_variant_card.html — styled printable card
A458T_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)
A458T_wildtype_interactions.pse / A458T_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 A458T 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 A458T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.