K634Q

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Lysine → Glutamine at position 634 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K634 — ionic bond to E403

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DynaMut2 mutant · K634Q

Mutant Q634 — ionic bond to E403 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E403	—	Lost
Hydrogen bond	E403	—	Lost
Hydrogen bond	S630	S630	Preserved
Hydrogen bond	S631	S631	Preserved
Hydrogen bond	V638	V638	Preserved
Polar contact	E403	—	Lost
Polar contact	—	H407	Gained
Polar contact	S630	S630	Preserved
Polar contact	S631	S631	Preserved
Polar contact	M632	M632	Preserved
Polar contact	L637	L637	Preserved
Polar contact	V638	V638	Preserved
Van der Waals	S630	S630	Preserved
Van der Waals	M632	—	Lost

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

-0.36kcal/mol

Destabilising — mild

AlphaMissense

0.730

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00043%

cDNA changec.1900A>C

ClinVar accessionVCV001382930

Last evaluated2024/04/19 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K634Q Variant Card

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

Lysine → Glutamine at position 634. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.730, DynaMut2 ΔΔG -0.36 kcal/mol (destabilising).

Identity

Field	Value
Variant	K634Q (p.Lysine634Glutamine)
DNA change	c.1900A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001382930
Amino acid change	Lysine (K) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 634	82.69 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 634 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 634 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 polar amide (glutamine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.7303
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.36 (Destabilising)
Job ID	178092122576
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092122576

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/04/19 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	K634Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.36 < 2 kcal/mol (fold intact) + AlphaMissense 0.730 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|=0.36 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.730. 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
K634Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 634 with ball-and-stick + neighbors within 5Å)
K634Q_variant_card.md — this card (source of truth)
K634Q_variant_card.html — styled printable card
K634Q_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)
K634Q_wildtype_interactions.pse / K634Q_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 K634Q 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 K634Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.