R868P

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

Arginine → Proline at position 868 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R868 — hydrogen bond to H872

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DynaMut2 mutant · R868P

Mutant P868 — polar contact contact to H872 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	E655	Gained
Hydrogen bond	H872	H872	Preserved
Polar contact	D866	—	Lost
Polar contact	H872	H872	Preserved
Van der Waals	D866	D866	Preserved
Van der Waals	T870	T870	Preserved
Van der Waals	H872	H872	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

0.72kcal/mol

Stabilising — mild

AlphaMissense

0.823

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram-like syndrome; Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Optic atrophy

Population frequency (gnomAD v4)Ultra-rare · AF 0.0012%

cDNA changec.2603G>C

ClinVar accessionVCV000931915

Last evaluated2024/05/08 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R868P Variant Card

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

Arginine → Proline at position 868. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.823, DynaMut2 ΔΔG +0.72 kcal/mol (stabilising).

Identity

Field	Value
Variant	R868P (p.Arginine868Proline)
DNA change	c.2603G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000931915
Amino acid change	Arginine (R) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 868	67.62 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 868 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 868 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 positively charged (arginine — guanidinium, strong H-bond donor); the mutant is rigid/helix-breaking (proline — kinks backbone). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8230
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.72 (Stabilising)
Job ID	178092113249
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092113249

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/05/08 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	R868P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.72 < 2 kcal/mol (fold intact) + AlphaMissense 0.823 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|=0.72 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.823. 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
R868P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 868 with ball-and-stick + neighbors within 5Å)
R868P_variant_card.md — this card (source of truth)
R868P_variant_card.html — styled printable card
R868P_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)
R868P_wildtype_interactions.pse / R868P_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 R868P 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 R868P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.