W700R

Category 2 — Moderately DestabilizingUncertain significanceLumenal · predictedσ-1 candidateSource card

Tryptophan → Arginine at position 700 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type W700 — hydrogen bond to F825

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DynaMut2 mutant · W700R

Mutant R700 — hydrogen bond to L664 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost6 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L664	—	Lost
Hydrogen bond	—	G702	Gained
Hydrogen bond	—	M781	Gained
Hydrogen bond	—	I823	Gained
Hydrogen bond	E824	E824	Preserved
Hydrogen bond	F825	F825	Preserved
Polar contact	L664	—	Lost
Polar contact	—	G702	Gained
Polar contact	—	M781	Gained
Polar contact	E824	E824	Preserved
Polar contact	F825	F825	Preserved
Aromatic / π	W666	—	Lost
Aromatic / π	Y669	—	Lost
Van der Waals	—	E824	Gained
Hydrophobic	W666	W666	Preserved
Hydrophobic	Y669	—	Lost
Hydrophobic	V698	—	Lost
Hydrophobic	M781	M781	Preserved
Hydrophobic	I802	—	Lost
Hydrophobic	F825	F825	Preserved
Hydrophobic	L829	—	Lost
Hydrophobic	F840	—	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

-2.17kcal/mol

Destabilising — large

AlphaMissense

1.000

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2098T>A

ClinVar accessionVCV002637634

Last evaluated2023/10/09 00:00

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

Full Variant Card

WFS1 Wolframin — W700R Variant Card

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

Tryptophan → Arginine at position 700. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 1.000, DynaMut2 ΔΔG -2.17 kcal/mol (destabilising).

Identity

Field	Value
Variant	W700R (p.Tryptophan700Arginine)
DNA change	c.2098T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002637634
Amino acid change	Tryptophan (W) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 700	90.19 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 700 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 700 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 bulky aromatic (tryptophan — indole ring); 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	0.9996
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.17 (Destabilising)
Job ID	178090203217
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178090203217

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/10/09 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	W700R 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.17 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
W700R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 700 with ball-and-stick + neighbors within 5Å)
W700R_variant_card.md — this card (source of truth)
W700R_variant_card.html — styled printable card
W700R_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)
W700R_wildtype_interactions.pse / W700R_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 W700R 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 W700R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.