C742Y

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

Cysteine → Tyrosine at position 742 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type C742 — hydrogen bond to C755

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DynaMut2 mutant · C742Y

Mutant Y742 — hydrogen bond contact to C755 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained2 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	C755	C755	Preserved
Polar contact	C755	C755	Preserved
Hydrophobic	—	P744	Gained
Hydrophobic	C755	—	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

-0.35kcal/mol

Destabilising — mild

AlphaMissense

0.930

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 conditionsWolfram syndrome 1; WFS1-Related Spectrum Disorders; Autosomal dominant nonsyndromic hearing loss 6

Population frequency (gnomAD v4)Ultra-rare · AF 0.00099%

cDNA changec.2225G>A

ClinVar accessionVCV000906717

Last evaluated2022/07/23 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — C742Y Variant Card

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

Cysteine → Tyrosine at position 742. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.930, DynaMut2 ΔΔG -0.35 kcal/mol (destabilising).

Identity

Field	Value
Variant	C742Y (p.Cysteine742Tyrosine)
DNA change	c.2225G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000906717
Amino acid change	Cysteine (C) → Tyrosine (Y)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 742	77.50 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 742 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 742 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	0.9300
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.35 (Destabilising)
Job ID	178092104073
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092104073

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2022/07/23 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	C742Y is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1
WFS1-Related Spectrum Disorders
Autosomal dominant nonsyndromic hearing loss 6

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|=0.35 < 2 kcal/mol (fold intact) + AlphaMissense 0.930 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|=0.35 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.930. 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
C742Y_molstar_viewer.html — interactive 3D viewer (auto-highlights position 742 with ball-and-stick + neighbors within 5Å)
C742Y_variant_card.md — this card (source of truth)
C742Y_variant_card.html — styled printable card
C742Y_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)
C742Y_wildtype_interactions.pse / C742Y_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 C742Y 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 C742Y PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.