K369T

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Lysine → Threonine at position 369 · Lumenal loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K369 — hydrogen bond to N373

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DynaMut2 mutant · K369T

Mutant T369 — polar contact contact to N373 lost

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F365	F365	Preserved
Hydrogen bond	Q366	Q366	Preserved
Hydrogen bond	E372	E372	Preserved
Hydrogen bond	N373	N373	Preserved
Polar contact	F365	F365	Preserved
Polar contact	Q366	Q366	Preserved
Polar contact	—	W371	Gained
Polar contact	E372	E372	Preserved
Polar contact	N373	N373	Preserved
Van der Waals	—	F365	Gained
Van der Waals	—	D367	Gained
Van der Waals	W371	W371	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

-0.40kcal/mol

Destabilising — mild

AlphaMissense

0.663

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 conditionsInborn genetic diseases; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00027%

cDNA changec.1106A>C

ClinVar accessionVCV000215377

Last evaluated2025/07/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K369T Variant Card

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

Lysine → Threonine at position 369. Lumenal loop 1. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.663, DynaMut2 ΔΔG -0.40 kcal/mol (destabilising).

Identity

Field	Value
Variant	K369T (p.Lysine369Threonine)
DNA change	c.1106A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000215377
Amino acid change	Lysine (K) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 369	74.88 — well-folded
Domain	Lumenal loop 1
Position context	C-terminal lumenal domain · position 369 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 369 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 positively charged (lysine — primary amine); 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	0.6630
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.4 (Destabilising)
Job ID	178092127822
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092127822

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/07/15 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	K369T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases
Wolfram syndrome 1

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|=0.40 < 2 kcal/mol (fold intact) + AlphaMissense 0.663 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|=0.40 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.663. 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
K369T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 369 with ball-and-stick + neighbors within 5Å)
K369T_variant_card.md — this card (source of truth)
K369T_variant_card.html — styled printable card
K369T_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)
K369T_wildtype_interactions.pse / K369T_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 K369T 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 K369T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.