I296T

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Isoleucine → Threonine at position 296 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I296 — hydrogen bond to K300

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DynaMut2 mutant · I296T

Mutant T296 — polar contact contact to P292 lost

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	P292	P292	Preserved
Hydrogen bond	—	L293	Gained
Hydrogen bond	K300	K300	Preserved
Polar contact	P292	P292	Preserved
Polar contact	—	L293	Gained
Polar contact	H294	H294	Preserved
Polar contact	—	I299	Gained
Polar contact	K300	K300	Preserved
Van der Waals	H294	H294	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

-0.85kcal/mol

Destabilising — mild

AlphaMissense

0.866

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00034%

cDNA changec.887T>C

ClinVar accessionVCV002781305

Last evaluated2024/01/14 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — I296T Variant Card

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

Isoleucine → Threonine at position 296. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.866, DynaMut2 ΔΔG -0.85 kcal/mol (destabilising).

Identity

Field	Value
Variant	I296T (p.Isoleucine296Threonine)
DNA change	c.887T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002781305
Amino acid change	Isoleucine (I) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 296	67.19 — confident
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 296 sits in N-terminal cytoplasmic (intrinsically disordered). 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	0.8661
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.85 (Destabilising)
Job ID	178092146285
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092146285

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/01/14 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	I296T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.85 < 2 kcal/mol (fold intact) + AlphaMissense 0.866 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|=0.85 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.866. 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
I296T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 296 with ball-and-stick + neighbors within 5Å)
I296T_variant_card.md — this card (source of truth)
I296T_variant_card.html — styled printable card
I296T_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)
I296T_wildtype_interactions.pse / I296T_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 I296T 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 I296T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.