A422P

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Alanine → Proline at position 422 · Lumenal loop 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A422 — hydrogen bond to S418

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DynaMut2 mutant · A422P

Mutant P422 — hydrogen bond to S418 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S418	—	Lost
Polar contact	S418	S418	Preserved
Polar contact	—	F419	Gained
Polar contact	K424	—	Lost
Van der Waals	S418	S418	Preserved
Hydrophobic	P346	P346	Preserved
Hydrophobic	L347	L347	Preserved
Hydrophobic	I427	I427	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

0.62kcal/mol

Stabilising — mild

AlphaMissense

0.945

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1264G>C

ClinVar accessionVCV003590687

Last evaluated2024/01/31 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A422P Variant Card

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

Alanine → Proline at position 422. Lumenal loop 2. ClinVar Uncertain significance, AlphaMissense 0.945, DynaMut2 ΔΔG +0.62 kcal/mol (stabilising).

Identity

Field	Value
Variant	A422P (p.Alanine422Proline)
DNA change	c.1264G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590687
Amino acid change	Alanine (A) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 422	87.12 — well-folded
Domain	Lumenal loop 2
Position context	C-terminal lumenal domain · position 422 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 422 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); 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	0.9450
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.62 (Stabilising)
Job ID	178092141883
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092141883

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/01/31 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A422P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.62 < 2 kcal/mol (fold intact) + AlphaMissense 0.945 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|=0.62 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.945. 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
A422P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 422 with ball-and-stick + neighbors within 5Å)
A422P_variant_card.md — this card (source of truth)
A422P_variant_card.html — styled printable card
A422P_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)
A422P_wildtype_interactions.pse / A422P_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 A422P 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 A422P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.