I332T

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

Isoleucine → Threonine at position 332 · Cytoplasmic loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I332 — hydrogen bond to I328

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DynaMut2 mutant · I332T

Mutant T332 — hydrogen bond to F329 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I328	I328	Preserved
Hydrogen bond	F329	F329	Preserved
Hydrogen bond	N335	N335	Preserved
Hydrogen bond	L336	L336	Preserved
Polar contact	I328	I328	Preserved
Polar contact	F329	F329	Preserved
Polar contact	S334	S334	Preserved
Polar contact	N335	N335	Preserved
Polar contact	L336	L336	Preserved
Van der Waals	S334	S334	Preserved
Van der Waals	N335	—	Lost
Hydrophobic	I328	—	Lost
Hydrophobic	L336	—	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

-1.32kcal/mol

Destabilising — moderate

AlphaMissense

0.411

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.00019%

cDNA changec.995T>C

ClinVar accessionVCV002231646

Last evaluated2021/06/19 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — I332T Variant Card

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

Isoleucine → Threonine at position 332. Cytoplasmic loop 1. ClinVar Uncertain significance, AlphaMissense 0.411, DynaMut2 ΔΔG -1.32 kcal/mol (destabilising).

Identity

Field	Value
Variant	I332T (p.Isoleucine332Threonine)
DNA change	c.995T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002231646
Amino acid change	Isoleucine (I) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 332	72.94 — well-folded
Domain	Cytoplasmic loop 1
Position context	Loop region · position 332 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 332 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 medium hydrophobic (isoleucine — branched); 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	0.4108
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.32 (Destabilising)
Job ID	178094716666
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094716666

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2021/06/19 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	I332T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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|=1.32 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.411. 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
I332T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 332 with ball-and-stick + neighbors within 5Å)
I332T_variant_card.md — this card (source of truth)
I332T_variant_card.html — styled printable card
I332T_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)
I332T_wildtype_interactions.pse / I332T_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 I332T 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 I332T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.