L410R

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Arginine at position 410 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L410 — hydrogen bond to A406

Fullscreen ↗

DynaMut2 mutant · L410R

Mutant R410 — hydrophobic contact to F414 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

0 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A406	A406	Preserved
Hydrogen bond	—	H407	Gained
Hydrogen bond	F413	F413	Preserved
Hydrogen bond	F414	F414	Preserved
Polar contact	A406	A406	Preserved
Polar contact	—	H407	Gained
Polar contact	F408	F408	Preserved
Polar contact	F413	F413	Preserved
Polar contact	F414	F414	Preserved
Van der Waals	F408	F408	Preserved
Hydrophobic	F414	F414	Preserved
Hydrophobic	L637	L637	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

-0.43kcal/mol

Destabilising — mild

AlphaMissense

0.934

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 conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1229T>G

ClinVar accessionVCV003637002

Last evaluated2024/08/14 00:00

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

Full Variant Card

WFS1 Wolframin — L410R Variant Card

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

Leucine → Arginine at position 410. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.934, DynaMut2 ΔΔG -0.43 kcal/mol (destabilising).

Identity

Field	Value
Variant	L410R (p.Leucine410Arginine)
DNA change	c.1229T>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003637002
Amino acid change	Leucine (L) → Arginine (R)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 410	91.31 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 410 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 410 sits in a transmembrane helix (Transmembrane helix 4). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is medium hydrophobic (leucine — branched); 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	0.9341
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.43 (Destabilising)
Job ID	178092102914
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092102914

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/08/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L410R 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.43 < 2 kcal/mol (fold intact) + AlphaMissense 0.934 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|=0.43 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.934. 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
L410R_molstar_viewer.html — interactive 3D viewer (auto-highlights position 410 with ball-and-stick + neighbors within 5Å)
L410R_variant_card.md — this card (source of truth)
L410R_variant_card.html — styled printable card
L410R_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)
L410R_wildtype_interactions.pse / L410R_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 L410R 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 L410R PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.