C765Y

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

Cysteine → Tyrosine at position 765 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type C765 — hydrogen bond to A738

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DynaMut2 mutant · C765Y

Mutant Y765 — hydrogen bond to A738 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost7 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	R732	Gained
Hydrogen bond	A738	—	Lost
Hydrogen bond	—	Y739	Gained
Polar contact	C733	C733	Preserved
Polar contact	E737	E737	Preserved
Polar contact	—	Y739	Gained
Polar contact	—	H763	Gained
Carbonyl	E737	E737	Preserved
Van der Waals	—	C733	Gained
Van der Waals	E737	—	Lost
Van der Waals	—	A738	Gained
Van der Waals	H763	—	Lost
Hydrophobic	R732	—	Lost
Hydrophobic	C733	C733	Preserved
Hydrophobic	—	A738	Gained

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

-0.42kcal/mol

Destabilising — mild

AlphaMissense

0.985

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 0.00025%

cDNA changec.2294G>A

ClinVar accessionVCV003373194

Last evaluated2024/04/29 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — C765Y Variant Card

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

Cysteine → Tyrosine at position 765. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.985, DynaMut2 ΔΔG -0.42 kcal/mol (destabilising).

Identity

Field	Value
Variant	C765Y (p.Cysteine765Tyrosine)
DNA change	c.2294G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003373194
Amino acid change	Cysteine (C) → Tyrosine (Y)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 765	89.19 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 765 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 765 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 thiol (cysteine — disulfide-capable, free -SH); the mutant is aromatic with hydroxyl (tyrosine — 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	0.9845
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.42 (Destabilising)
Job ID	178092090965
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092090965

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/04/29 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	C765Y 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|=0.42 < 2 kcal/mol (fold intact) + AlphaMissense 0.985 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|=0.42 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.985. 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
C765Y_molstar_viewer.html — interactive 3D viewer (auto-highlights position 765 with ball-and-stick + neighbors within 5Å)
C765Y_variant_card.md — this card (source of truth)
C765Y_variant_card.html — styled printable card
C765Y_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)
C765Y_wildtype_interactions.pse / C765Y_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 C765Y 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 C765Y PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.