T827I

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

Threonine → Isoleucine at position 827 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T827 — hydrogen bond to V698

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DynaMut2 mutant · T827I

Mutant I827 — hydrogen bond to R697 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost6 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R697	—	Lost
Hydrogen bond	V698	V698	Preserved
Hydrogen bond	F840	—	Lost
Hydrogen bond	—	E841	Gained
Polar contact	V698	V698	Preserved
Polar contact	F840	—	Lost
Polar contact	E841	E841	Preserved
Van der Waals	—	F825	Gained
Van der Waals	—	E841	Gained
Hydrophobic	V698	V698	Preserved
Hydrophobic	—	W700	Gained
Hydrophobic	—	L804	Gained
Hydrophobic	F825	F825	Preserved
Hydrophobic	F840	F840	Preserved
Hydrophobic	—	L842	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

0.56kcal/mol

Stabilising — mild

AlphaMissense

0.912

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1; Type 2 diabetes mellitus

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2480C>T

ClinVar accessionVCV000930354

Last evaluated2016/01/01 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — T827I Variant Card

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

Threonine → Isoleucine at position 827. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.912, DynaMut2 ΔΔG +0.56 kcal/mol (stabilising).

Identity

Field	Value
Variant	T827I (p.Threonine827Isoleucine)
DNA change	c.2480C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000930354
Amino acid change	Threonine (T) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 827	88.19 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 827 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 827 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	0.9116
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.56 (Stabilising)
Job ID	178092145594
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092145594

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2016/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	T827I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1
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|=0.56 < 2 kcal/mol (fold intact) + AlphaMissense 0.912 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|=0.56 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.912. 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
T827I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 827 with ball-and-stick + neighbors within 5Å)
T827I_variant_card.md — this card (source of truth)
T827I_variant_card.html — styled printable card
T827I_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)
T827I_wildtype_interactions.pse / T827I_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 T827I 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 T827I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.