L637P

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Leucine → Proline at position 637 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L637 — hydrogen bond to T641

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DynaMut2 mutant · L637P

Mutant P637 — hydrogen bond to L640 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S411	—	Lost
Hydrogen bond	V633	V633	Preserved
Hydrogen bond	L640	—	Lost
Hydrogen bond	T641	T641	Preserved
Polar contact	V633	V633	Preserved
Polar contact	K634	—	Lost
Polar contact	L635	—	Lost
Polar contact	L640	L640	Preserved
Polar contact	T641	T641	Preserved
Van der Waals	—	V633	Gained
Van der Waals	L635	—	Lost
Van der Waals	—	W639	Gained
Van der Waals	T641	—	Lost
Hydrophobic	H407	—	Lost
Hydrophobic	L410	L410	Preserved
Hydrophobic	F414	—	Lost
Hydrophobic	V633	—	Lost
Hydrophobic	—	L640	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

-0.52kcal/mol

Destabilising — mild

AlphaMissense

0.960

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)Absent from gnomAD v4

cDNA changec.1910T>C

ClinVar accessionVCV001318843

Last evaluated2019/08/16 00:00

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

Full Variant Card

WFS1 Wolframin — L637P Variant Card

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

Leucine → Proline at position 637. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.960, DynaMut2 ΔΔG -0.52 kcal/mol (destabilising).

Identity

Field	Value
Variant	L637P (p.Leucine637Proline)
DNA change	c.1910T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001318843
Amino acid change	Leucine (L) → Proline (P)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 637	85.44 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 637 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 637 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	0.9595
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.52 (Destabilising)
Job ID	178092098628
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092098628

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2019/08/16 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L637P 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|=0.52 < 2 kcal/mol (fold intact) + AlphaMissense 0.960 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|=0.52 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.960. 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
L637P_molstar_viewer.html — interactive 3D viewer (auto-highlights position 637 with ball-and-stick + neighbors within 5Å)
L637P_variant_card.md — this card (source of truth)
L637P_variant_card.html — styled printable card
L637P_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)
L637P_wildtype_interactions.pse / L637P_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 L637P 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 L637P PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.