I845T

Category 2 — Moderately DestabilizingUncertain significanceLumenal · predictedσ-1 candidateSource card

Isoleucine → Threonine at position 845 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I845 — hydrogen bond to V861

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DynaMut2 mutant · I845T

Mutant T845 — van der waals to V861 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E824	E824	Preserved
Hydrogen bond	H860	H860	Preserved
Hydrogen bond	V861	V861	Preserved
Polar contact	E824	E824	Preserved
Polar contact	H860	H860	Preserved
Polar contact	V861	V861	Preserved
Carbonyl	E824	E824	Preserved
Van der Waals	V861	V861	Preserved
Hydrophobic	F810	F810	Preserved
Hydrophobic	V813	V813	Preserved
Hydrophobic	L814	—	Lost
Hydrophobic	L817	—	Lost
Hydrophobic	I823	—	Lost
Hydrophobic	L842	L842	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

-2.33kcal/mol

Destabilising — large

AlphaMissense

0.944

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

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

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2534T>C

ClinVar accessionVCV003590746

Last evaluated2024/05/14 00:00

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

Full Variant Card

WFS1 Wolframin — I845T Variant Card

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

Isoleucine → Threonine at position 845. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.944, DynaMut2 ΔΔG -2.33 kcal/mol (destabilising).

Identity

Field	Value
Variant	I845T (p.Isoleucine845Threonine)
DNA change	c.2534T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590746
Amino acid change	Isoleucine (I) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 845	89.25 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 845 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 845 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 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	0.9439
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.33 (Destabilising)
Job ID	178092101091
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092101091

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/05/14 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	I845T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6
Cataract 41
Wolfram syndrome 1
Wolfram-like syndrome
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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.33 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
I845T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 845 with ball-and-stick + neighbors within 5Å)
I845T_variant_card.md — this card (source of truth)
I845T_variant_card.html — styled printable card
I845T_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)
I845T_wildtype_interactions.pse / I845T_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 I845T 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 I845T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.