C604R

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Cysteine → Arginine at position 604 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type C604 — hydrogen bond to T600

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DynaMut2 mutant · C604R

Mutant R604 — polar contact to T600 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T600	T600	Preserved
Hydrogen bond	P607	P607	Preserved
Hydrogen bond	L608	L608	Preserved
Polar contact	T600	T600	Preserved
Polar contact	V601	V601	Preserved
Polar contact	V606	V606	Preserved
Polar contact	P607	P607	Preserved
Van der Waals	T600	—	Lost
Van der Waals	V606	—	Lost
Van der Waals	—	P607	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

0.37kcal/mol

Stabilising — mild

AlphaMissense

0.970

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 conditionsAutosomal dominant nonsyndromic hearing loss 6; Cataract 41; Wolfram syndrome 1; Wolfram-like syndrome; Type 2 diabetes mellitus

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1810T>C

ClinVar accessionVCV003590711

Last evaluated2024/05/08 00:00

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

Full Variant Card

WFS1 Wolframin — C604R Variant Card

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

Cysteine → Arginine at position 604. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.970, DynaMut2 ΔΔG +0.37 kcal/mol (stabilising).

Identity

Field	Value
Variant	C604R (p.Cysteine604Arginine)
DNA change	c.1810T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590711
Amino acid change	Cysteine (C) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 604	72.50 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 604 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 604 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 positively charged (arginine — guanidinium, strong H-bond donor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9701
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.37 (Stabilising)
Job ID	178092097025
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092097025

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/05/08 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	C604R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6
Cataract 41
Wolfram syndrome 1
Wolfram-like syndrome
Type 2 diabetes mellitus

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|=0.37 < 2 kcal/mol (fold intact) + AlphaMissense 0.970 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|=0.37 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.970. 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
C604R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 604 with ball-and-stick + neighbors within 5Å)
C604R_variant_card.md — this card (source of truth)
C604R_variant_card.html — styled printable card
C604R_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)
C604R_wildtype_interactions.pse / C604R_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 C604R 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 C604R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.