R456L

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Arginine → Leucine at position 456 · Cytoplasmic loop 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R456 — hydrogen bond to E452

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DynaMut2 mutant · R456L

Mutant L456 — energy-minimized; 3 new contacts formed

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E452	E452	Preserved
Hydrogen bond	A460	A460	Preserved
Polar contact	—	Y444	Gained
Polar contact	E452	E452	Preserved
Polar contact	A460	A460	Preserved
Van der Waals	—	Y444	Gained
Van der Waals	—	A460	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

0.22kcal/mol

Stabilising — mild

AlphaMissense

0.392

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1367G>T

ClinVar accessionVCV002998407

Last evaluated2023/02/13 00:00

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

Full Variant Card

WFS1 Wolframin — R456L Variant Card

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

Arginine → Leucine at position 456. Cytoplasmic loop 3. ClinVar Uncertain significance, AlphaMissense 0.392, DynaMut2 ΔΔG +0.22 kcal/mol (stabilising).

Identity

Field	Value
Variant	R456L (p.Arginine456Leucine)
DNA change	c.1367G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002998407
Amino acid change	Arginine (R) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 456	85.69 — well-folded
Domain	Cytoplasmic loop 3
Position context	Loop region · position 456 sits between transmembrane segments, solvent-accessible
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 456 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); the mutant is medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3920
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.22 (Stabilising)
Job ID	178094718383
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094718383

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/02/13 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R456L 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|=0.22 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.22 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.392. 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
R456L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 456 with ball-and-stick + neighbors within 5Å)
R456L_variant_card.md — this card (source of truth)
R456L_variant_card.html — styled printable card
R456L_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)
R456L_wildtype_interactions.pse / R456L_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 R456L 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 R456L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.