R708H

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

Arginine → Histidine at position 708 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R708 — ionic bond to E776

Fullscreen ↗

DynaMut2 mutant · R708H

Mutant H708 — ionic bond to E776 lost (7 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

7 lost2 gained3 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E776	—	Lost
Hydrogen bond	F775	F775	Preserved
Hydrogen bond	E776	E776	Preserved
Polar contact	—	T710	Gained
Polar contact	F775	—	Lost
Polar contact	E776	E776	Preserved
Aromatic / π	—	Y706	Gained
Carbonyl	F775	—	Lost
Van der Waals	F775	—	Lost
Van der Waals	E776	—	Lost
Hydrophobic	T710	—	Lost
Hydrophobic	E776	—	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

-1.18kcal/mol

Destabilising — moderate

AlphaMissense

0.808

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 syndrome 1

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

cDNA changec.2123G>A

ClinVar accessionVCV002503272

Last evaluated2025/05/11 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R708H Variant Card

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

Arginine → Histidine at position 708. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.808, DynaMut2 ΔΔG -1.18 kcal/mol (destabilising).

Identity

Field	Value
Variant	R708H (p.Arginine708Histidine)
DNA change	c.2123G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002503272
Amino acid change	Arginine (R) → Histidine (H)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 708	93.44 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 708 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 708 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 titratable basic (histidine — imidazole). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8078
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.18 (Destabilising)
Job ID	178092148801
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092148801

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/05/11 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	R708H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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|=1.18 < 2 kcal/mol (fold intact) + AlphaMissense 0.808 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|=1.18 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.808. 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
R708H_molstar_viewer.html — interactive 3D viewer (auto-highlights position 708 with ball-and-stick + neighbors within 5Å)
R708H_variant_card.md — this card (source of truth)
R708H_variant_card.html — styled printable card
R708H_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)
R708H_wildtype_interactions.pse / R708H_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 R708H 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 R708H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.