T600I

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

Threonine → Isoleucine at position 600 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T600 — hydrogen bond to I597

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DynaMut2 mutant · T600I

Mutant I600 — hydrogen bond to I597 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K596	K596	Preserved
Hydrogen bond	I597	—	Lost
Hydrogen bond	—	V603	Gained
Hydrogen bond	C604	C604	Preserved
Polar contact	K596	K596	Preserved
Polar contact	I597	I597	Preserved
Polar contact	—	A602	Gained
Polar contact	V603	V603	Preserved
Polar contact	C604	C604	Preserved
Van der Waals	W588	W588	Preserved
Van der Waals	A602	A602	Preserved
Van der Waals	C604	—	Lost
Hydrophobic	W588	W588	Preserved
Hydrophobic	L592	L592	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

-0.27kcal/mol

Destabilising — mild

AlphaMissense

0.347

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 conditionsAutosomal dominant nonsyndromic hearing loss 6; WFS1-Related Spectrum Disorders

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

cDNA changec.1799C>T

ClinVar accessionVCV000349319

Last evaluated2018/01/12 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T600I Variant Card

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

Threonine → Isoleucine at position 600. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.347, DynaMut2 ΔΔG -0.27 kcal/mol (destabilising).

Identity

Field	Value
Variant	T600I (p.Threonine600Isoleucine)
DNA change	c.1799C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000349319
Amino acid change	Threonine (T) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 600	69.38 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 600 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 600 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	0.3473
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.27 (Destabilising)
Job ID	178094721319
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094721319

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2018/01/12 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	T600I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6
WFS1-Related Spectrum Disorders

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|=0.27 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.27 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.347. 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
T600I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 600 with ball-and-stick + neighbors within 5Å)
T600I_variant_card.md — this card (source of truth)
T600I_variant_card.html — styled printable card
T600I_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)
T600I_wildtype_interactions.pse / T600I_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 T600I 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 T600I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.