Y660C

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Tyrosine → Cysteine at position 660 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type Y660 — hydrogen bond to S662

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DynaMut2 mutant · Y660C

Mutant C660 — hydrogen bond contact to S662 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S662	—	Lost
Hydrogen bond	G695	G695	Preserved
Hydrogen bond	H696	H696	Preserved
Hydrogen bond	R697	R697	Preserved
Polar contact	K658	K658	Preserved
Polar contact	S662	S662	Preserved
Polar contact	G695	G695	Preserved
Polar contact	—	H696	Gained
Polar contact	R697	R697	Preserved
Van der Waals	G695	G695	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

0.87kcal/mol

Stabilising — mild

AlphaMissense

0.960

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%

cDNA changec.1979A>G

ClinVar accessionVCV002062418

Last evaluated2022/08/16 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — Y660C Variant Card

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

Tyrosine → Cysteine at position 660. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.960, DynaMut2 ΔΔG +0.87 kcal/mol (stabilising).

Identity

Field	Value
Variant	Y660C (p.Tyrosine660Cysteine)
DNA change	c.1979A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002062418
Amino acid change	Tyrosine (Y) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 660	62.75 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 660 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 660 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 aromatic with hydroxyl (tyrosine — H-bond donor/acceptor); the mutant is thiol (cysteine — disulfide-capable, free -SH). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9597
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.87 (Stabilising)
Job ID	178092098459
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092098459

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/08/16 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	Y660C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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|=0.87 < 2 kcal/mol (fold intact) + AlphaMissense 0.960 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|=0.87 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.960. 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
Y660C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 660 with ball-and-stick + neighbors within 5Å)
Y660C_variant_card.md — this card (source of truth)
Y660C_variant_card.html — styled printable card
Y660C_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)
Y660C_wildtype_interactions.pse / Y660C_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 Y660C 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 Y660C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.