T778I

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Threonine → Isoleucine at position 778 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T778 — hydrogen bond to Y706

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DynaMut2 mutant · T778I

Mutant I778 — hydrogen bond contact to Y706 lost

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K705	K705	Preserved
Hydrogen bond	Y706	Y706	Preserved
Hydrogen bond	I802	I802	Preserved
Polar contact	K705	K705	Preserved
Polar contact	Y706	Y706	Preserved
Polar contact	I802	I802	Preserved
Van der Waals	—	K705	Gained
Van der Waals	Y706	Y706	Preserved
Hydrophobic	K705	K705	Preserved
Hydrophobic	Y706	Y706	Preserved
Hydrophobic	D801	D801	Preserved
Hydrophobic	—	V803	Gained
Hydrophobic	—	W837	Gained

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

0.05kcal/mol

Stabilising — mild

AlphaMissense

0.900

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 conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00048%

cDNA changec.2333C>T

ClinVar accessionVCV001321085

Last evaluated2025/12/23 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T778I Variant Card

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

Threonine → Isoleucine at position 778. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.900, DynaMut2 ΔΔG +0.05 kcal/mol (stabilising).

Identity

Field	Value
Variant	T778I (p.Threonine778Isoleucine)
DNA change	c.2333C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001321085
Amino acid change	Threonine (T) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 778	91.44 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 778 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 778 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is small polar (threonine — hydroxyl); the mutant is medium hydrophobic (isoleucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8996
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.05 (Stabilising)
Job ID	178092108138
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092108138

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/12/23 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	T778I 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|=0.05 < 2 kcal/mol (fold intact) + AlphaMissense 0.900 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|=0.05 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.900. 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
T778I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 778 with ball-and-stick + neighbors within 5Å)
T778I_variant_card.md — this card (source of truth)
T778I_variant_card.html — styled printable card
T778I_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)
T778I_wildtype_interactions.pse / T778I_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 T778I 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 T778I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.