L609Q

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

Leucine → Glutamine at position 609 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L609 — hydrogen bond to S605

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DynaMut2 mutant · L609Q

Mutant Q609 — hydrogen bond to W613 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S605	S605	Preserved
Hydrogen bond	V606	V606	Preserved
Hydrogen bond	W612	—	Lost
Hydrogen bond	W613	W613	Preserved
Polar contact	S605	S605	Preserved
Polar contact	V606	V606	Preserved
Polar contact	W612	W612	Preserved
Polar contact	W613	W613	Preserved
Van der Waals	S605	S605	Preserved
Van der Waals	W613	W613	Preserved
Hydrophobic	W612	—	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

-0.16kcal/mol

Destabilising — mild

AlphaMissense

0.489

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 conditionsWFS1-related disorder

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1826T>A

ClinVar accessionVCV002637190

Last evaluated2022/10/14 00:00

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

Full Variant Card

WFS1 Wolframin — L609Q Variant Card

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

Leucine → Glutamine at position 609. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.489, DynaMut2 ΔΔG -0.16 kcal/mol (destabilising).

Identity

Field	Value
Variant	L609Q (p.Leucine609Glutamine)
DNA change	c.1826T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002637190
Amino acid change	Leucine (L) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 609	70.25 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 609 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 609 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 (leucine — branched); 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	0.4895
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.16 (Destabilising)
Job ID	178094734084
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094734084

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/10/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L609Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-related disorder

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|=0.16 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.16 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.489. 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
L609Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 609 with ball-and-stick + neighbors within 5Å)
L609Q_variant_card.md — this card (source of truth)
L609Q_variant_card.html — styled printable card
L609Q_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)
L609Q_wildtype_interactions.pse / L609Q_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 L609Q 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 L609Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.