L645P

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Proline at position 645 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L645 — hydrogen bond to T641

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DynaMut2 mutant · L645P

Mutant P645 — hydrogen bond to T641 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T641	T641	Preserved
Hydrogen bond	A642	—	Lost
Hydrogen bond	W648	W648	Preserved
Hydrogen bond	F649	F649	Preserved
Polar contact	T641	T641	Preserved
Polar contact	A642	—	Lost
Polar contact	W648	—	Lost
Polar contact	F649	F649	Preserved
Van der Waals	T641	—	Lost
Van der Waals	—	C647	Gained
Van der Waals	—	F649	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

-0.10kcal/mol

Destabilising — mild

AlphaMissense

0.827

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 conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1934T>C

ClinVar accessionVCV002672987

Last evaluated2024/04/15 00:00

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

Full Variant Card

WFS1 Wolframin — L645P Variant Card

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

Leucine → Proline at position 645. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.827, DynaMut2 ΔΔG -0.10 kcal/mol (destabilising).

Identity

Field	Value
Variant	L645P (p.Leucine645Proline)
DNA change	c.1934T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002672987
Amino acid change	Leucine (L) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 645	83.75 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 645 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 645 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 medium hydrophobic (leucine — branched); 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	0.8274
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.1 (Destabilising)
Job ID	178092146931
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092146931

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/04/15 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L645P 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|=0.10 < 2 kcal/mol (fold intact) + AlphaMissense 0.827 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|=0.10 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.827. 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
L645P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 645 with ball-and-stick + neighbors within 5Å)
L645P_variant_card.md — this card (source of truth)
L645P_variant_card.html — styled printable card
L645P_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)
L645P_wildtype_interactions.pse / L645P_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 L645P 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 L645P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.