P420L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Proline → Leucine at position 420 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type P420 — hydrogen bond to F417

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DynaMut2 mutant · P420L

Mutant L420 — hydrogen bond to F417 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained2 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F417	—	Lost
Polar contact	I416	—	Lost
Polar contact	—	S418	Gained
Polar contact	—	A422	Gained
Van der Waals	—	F877	Gained
Hydrophobic	A874	A874	Preserved
Hydrophobic	F877	F877	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

-0.19kcal/mol

Destabilising — mild

AlphaMissense

0.907

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1259C>T

ClinVar accessionVCV003981553

Last evaluated2025/06/12 00:00

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

Full Variant Card

WFS1 Wolframin — P420L Variant Card

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

Proline → Leucine at position 420. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.907, DynaMut2 ΔΔG -0.19 kcal/mol (destabilising).

Identity

Field	Value
Variant	P420L (p.Proline420Leucine)
DNA change	c.1259C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003981553
Amino acid change	Proline (P) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 420	87.56 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 420 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 420 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 rigid/helix-breaking (proline — kinks backbone); 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	0.9073
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.19 (Destabilising)
Job ID	178092106346
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092106346

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/06/12 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	P420L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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|=0.19 < 2 kcal/mol (fold intact) + AlphaMissense 0.907 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|=0.19 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.907. 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
P420L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 420 with ball-and-stick + neighbors within 5Å)
P420L_variant_card.md — this card (source of truth)
P420L_variant_card.html — styled printable card
P420L_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)
P420L_wildtype_interactions.pse / P420L_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 P420L 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 P420L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.