Y773C

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Tyrosine → Cysteine at position 773 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type Y773 — hydrogen bond to S808

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DynaMut2 mutant · Y773C

Mutant C773 — hydrogen bond to D771 lost (8 contacts lost)

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Bond changes · DynaMut2 interaction analysis

8 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	D711	D711	Preserved
Hydrogen bond	—	I712	Gained
Hydrogen bond	D771	—	Lost
Hydrogen bond	S808	S808	Preserved
Polar contact	—	D711	Gained
Polar contact	D771	—	Lost
Polar contact	—	F775	Gained
Polar contact	S808	S808	Preserved
Carbonyl	S807	—	Lost
Van der Waals	D771	—	Lost
Van der Waals	F775	—	Lost
Van der Waals	S808	S808	Preserved
Hydrophobic	V709	V709	Preserved
Hydrophobic	I712	—	Lost
Hydrophobic	D771	—	Lost
Hydrophobic	F775	F775	Preserved
Hydrophobic	K811	—	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

Stabilising — mild

AlphaMissense

0.434

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00075%

cDNA changec.2318A>G

ClinVar accessionVCV001438868

Last evaluated2024/12/19 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — Y773C Variant Card

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

Tyrosine → Cysteine at position 773. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.434, DynaMut2 ΔΔG +0.16 kcal/mol (stabilising).

Identity

Field	Value
Variant	Y773C (p.Tyrosine773Cysteine)
DNA change	c.2318A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001438868
Amino acid change	Tyrosine (Y) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 773	90.12 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 773 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 773 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	0.4338
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.16 (Stabilising)
Job ID	178094721667
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094721667

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/12/19 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	Y773C 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 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 0.434. 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
Y773C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 773 with ball-and-stick + neighbors within 5Å)
Y773C_variant_card.md — this card (source of truth)
Y773C_variant_card.html — styled printable card
Y773C_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)
Y773C_wildtype_interactions.pse / Y773C_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 Y773C 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 Y773C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.