A393T

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Alanine → Threonine at position 393 · Cytoplasmic loop 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A393 — hydrogen bond to V390

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DynaMut2 mutant · A393T

Mutant T393 — hydrogen bond contact to V390 lost

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained14 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	F374	Gained
Hydrogen bond	D389	D389	Preserved
Hydrogen bond	V390	V390	Preserved
Hydrogen bond	N396	N396	Preserved
Hydrogen bond	F397	F397	Preserved
Polar contact	—	F374	Gained
Polar contact	D389	D389	Preserved
Polar contact	V390	V390	Preserved
Polar contact	E391	E391	Preserved
Polar contact	V395	V395	Preserved
Polar contact	N396	N396	Preserved
Polar contact	F397	F397	Preserved
Van der Waals	—	F374	Gained
Van der Waals	E391	E391	Preserved
Van der Waals	V395	V395	Preserved
Hydrophobic	L172	L172	Preserved
Hydrophobic	F374	F374	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

-1.89kcal/mol

Destabilising — moderate

AlphaMissense

0.710

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000062%

cDNA changec.1177G>A

ClinVar accessionVCV001979339

Last evaluated2022/04/26 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A393T Variant Card

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

Alanine → Threonine at position 393. Cytoplasmic loop 2. ClinVar Uncertain significance, AlphaMissense 0.710, DynaMut2 ΔΔG -1.89 kcal/mol (destabilising).

Identity

Field	Value
Variant	A393T (p.Alanine393Threonine)
DNA change	c.1177G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001979339
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 393	79.88 — well-folded
Domain	Cytoplasmic loop 2
Position context	Loop region · position 393 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 393 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	0.7098
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.89 (Destabilising)
Job ID	178092125261
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092125261

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/04/26 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A393T 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.89 < 2 kcal/mol (fold intact) + AlphaMissense 0.710 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|=1.89 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.710. 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
A393T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 393 with ball-and-stick + neighbors within 5Å)
A393T_variant_card.md — this card (source of truth)
A393T_variant_card.html — styled printable card
A393T_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)
A393T_wildtype_interactions.pse / A393T_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 A393T 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 A393T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.