L381P

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Proline at position 381 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L381 — hydrogen bond to E385

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DynaMut2 mutant · L381P

Mutant P381 — hydrogen bond to L377 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L377	L377	Preserved
Hydrogen bond	T378	—	Lost
Hydrogen bond	F384	F384	Preserved
Hydrogen bond	E385	E385	Preserved
Polar contact	L377	L377	Preserved
Polar contact	T378	—	Lost
Polar contact	R383	R383	Preserved
Polar contact	F384	F384	Preserved
Polar contact	E385	E385	Preserved
Hydrophobic	V176	—	Lost
Hydrophobic	A179	A179	Preserved
Hydrophobic	T251	—	Lost
Hydrophobic	L377	L377	Preserved
Hydrophobic	L388	L388	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

-0.73kcal/mol

Destabilising — mild

AlphaMissense

0.997

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1142T>C

ClinVar accessionVCV000212610

Last evaluated2015/04/30 00:00

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

Full Variant Card

WFS1 Wolframin — L381P Variant Card

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

Leucine → Proline at position 381. Transmembrane helix 3. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.997, DynaMut2 ΔΔG -0.73 kcal/mol (destabilising).

Identity

Field	Value
Variant	L381P (p.Leucine381Proline)
DNA change	c.1142T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000212610
Amino acid change	Leucine (L) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 381	84.62 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 381 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 381 sits in a transmembrane helix (Transmembrane helix 3). 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 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	0.9973
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.73 (Destabilising)
Job ID	178092085951
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092085951

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2015/04/30 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	L381P 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|=0.73 < 2 kcal/mol (fold intact) + AlphaMissense 0.997 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|=0.73 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.997. 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
L381P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 381 with ball-and-stick + neighbors within 5Å)
L381P_variant_card.md — this card (source of truth)
L381P_variant_card.html — styled printable card
L381P_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)
L381P_wildtype_interactions.pse / L381P_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 L381P 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 L381P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.