A874P

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Alanine → Proline at position 874 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A874 — hydrogen bond to A878

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DynaMut2 mutant · A874P

Mutant P874 — hydrogen bond to V871 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T870	—	Lost
Hydrogen bond	V871	—	Lost
Hydrogen bond	F877	F877	Preserved
Hydrogen bond	A878	A878	Preserved
Polar contact	T870	T870	Preserved
Polar contact	V871	—	Lost
Polar contact	H872	—	Lost
Polar contact	F877	—	Lost
Polar contact	A878	A878	Preserved
Van der Waals	—	P420	Gained
Van der Waals	V871	—	Lost
Van der Waals	H872	—	Lost
Van der Waals	—	K876	Gained
Van der Waals	—	A878	Gained
Hydrophobic	P420	P420	Preserved
Hydrophobic	I421	I421	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

0.53kcal/mol

Stabilising — mild

AlphaMissense

0.912

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)Ultra-rare · AF 0.00034%

cDNA changec.2620G>C

ClinVar accessionVCV001320979

Last evaluated2021/04/27 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A874P Variant Card

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

Alanine → Proline at position 874. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.912, DynaMut2 ΔΔG +0.53 kcal/mol (stabilising).

Identity

Field	Value
Variant	A874P (p.Alanine874Proline)
DNA change	c.2620G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001320979
Amino acid change	Alanine (A) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 874	83.75 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 874 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 874 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	0.9124
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.53 (Stabilising)
Job ID	178092105226
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092105226

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2021/04/27 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A874P 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|=0.53 < 2 kcal/mol (fold intact) + AlphaMissense 0.912 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|=0.53 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.912. 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
A874P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 874 with ball-and-stick + neighbors within 5Å)
A874P_variant_card.md — this card (source of truth)
A874P_variant_card.html — styled printable card
A874P_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)
A874P_wildtype_interactions.pse / A874P_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 A874P 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 A874P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.