P404L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Proline → Leucine at position 404 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type P404 — hydrogen bond to F408

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DynaMut2 mutant · P404L

Mutant L404 — hydrogen bond to D367 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost5 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	D367	—	Lost
Hydrogen bond	H401	—	Lost
Hydrogen bond	—	H407	Gained
Hydrogen bond	F408	F408	Preserved
Polar contact	—	D367	Gained
Polar contact	H401	H401	Preserved
Polar contact	—	L402	Gained
Polar contact	H407	H407	Preserved
Polar contact	F408	F408	Preserved
Van der Waals	H401	—	Lost
Van der Waals	L402	—	Lost
Hydrophobic	K363	K363	Preserved
Hydrophobic	V364	V364	Preserved
Hydrophobic	—	D367	Gained
Hydrophobic	—	H401	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

-0.58kcal/mol

Destabilising — mild

AlphaMissense

0.874

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome

Population frequency (gnomAD v4)Ultra-rare · AF 0.00087%

cDNA changec.1211C>T

ClinVar accessionVCV001378120

Last evaluated2024/11/16 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — P404L Variant Card

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

Proline → Leucine at position 404. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.874, DynaMut2 ΔΔG -0.58 kcal/mol (destabilising).

Identity

Field	Value
Variant	P404L (p.Proline404Leucine)
DNA change	c.1211C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001378120
Amino acid change	Proline (P) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 404	87.75 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 404 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 404 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	0.8743
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.58 (Destabilising)
Job ID	178092109516
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092109516

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/11/16 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	P404L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1
Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
Wolfram-like syndrome

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|=0.58 < 2 kcal/mol (fold intact) + AlphaMissense 0.874 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|=0.58 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.874. 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
P404L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 404 with ball-and-stick + neighbors within 5Å)
P404L_variant_card.md — this card (source of truth)
P404L_variant_card.html — styled printable card
P404L_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)
P404L_wildtype_interactions.pse / P404L_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 P404L 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 P404L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.