P740H

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Proline → Histidine at position 740 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type P740 — polar contact to C755

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DynaMut2 mutant · P740H

Mutant H740 — van der waals to C755 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost1 gained1 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Polar contact	—	A738	Gained
Polar contact	C755	C755	Preserved
Van der Waals	C755	—	Lost
Hydrophobic	L754	—	Lost

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

-1.35kcal/mol

Destabilising — moderate

AlphaMissense

0.414

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%

cDNA changec.2219C>A

ClinVar accessionVCV004764471

Last evaluated2025/04/27 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — P740H Variant Card

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

Proline → Histidine at position 740. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.414, DynaMut2 ΔΔG -1.35 kcal/mol (destabilising).

Identity

Field	Value
Variant	P740H (p.Proline740Histidine)
DNA change	c.2219C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004764471
Amino acid change	Proline (P) → Histidine (H)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 740	84.88 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 740 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 740 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 rigid/helix-breaking (proline — kinks backbone); the mutant is titratable basic (histidine — imidazole). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4140
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.35 (Destabilising)
Job ID	178094721487
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094721487

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/04/27 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	P740H 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.35 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.35 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.414. 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
P740H_molstar_viewer.html — interactive 3D viewer (auto-highlights position 740 with ball-and-stick + neighbors within 5Å)
P740H_variant_card.md — this card (source of truth)
P740H_variant_card.html — styled printable card
P740H_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)
P740H_wildtype_interactions.pse / P740H_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 P740H 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 P740H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.