F365L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Leucine at position 365 · Lumenal loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F365 — hydrogen bond to S368

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DynaMut2 mutant · F365L

Mutant L365 — hydrogen bond to S368 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T361	T361	Preserved
Hydrogen bond	L362	L362	Preserved
Hydrogen bond	S368	—	Lost
Hydrogen bond	K369	K369	Preserved
Hydrogen bond	S443	—	Lost
Polar contact	T361	T361	Preserved
Polar contact	L362	L362	Preserved
Polar contact	K363	K363	Preserved
Polar contact	S368	S368	Preserved
Polar contact	K369	K369	Preserved
Polar contact	S443	—	Lost
Polar contact	S446	—	Lost
Van der Waals	K363	K363	Preserved
Hydrophobic	—	L362	Gained
Hydrophobic	F439	—	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

-1.32kcal/mol

Destabilising — moderate

AlphaMissense

0.977

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 conditionsInborn genetic diseases

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

cDNA changec.1093T>C

ClinVar accessionVCV003981550

Last evaluated2025/06/03 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F365L Variant Card

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

Phenylalanine → Leucine at position 365. Lumenal loop 1. ClinVar Uncertain significance, AlphaMissense 0.977, DynaMut2 ΔΔG -1.32 kcal/mol (destabilising).

Identity

Field	Value
Variant	F365L (p.Phenylalanine365Leucine)
DNA change	c.1093T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003981550
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 365	83.56 — well-folded
Domain	Lumenal loop 1
Position context	C-terminal lumenal domain · position 365 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 365 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 large aromatic hydrophobic (phenylalanine); the mutant is medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9772
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.32 (Destabilising)
Job ID	178092094661
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092094661

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/06/03 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	F365L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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|=1.32 < 2 kcal/mol (fold intact) + AlphaMissense 0.977 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|=1.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.977. 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
F365L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 365 with ball-and-stick + neighbors within 5Å)
F365L_variant_card.md — this card (source of truth)
F365L_variant_card.html — styled printable card
F365L_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)
F365L_wildtype_interactions.pse / F365L_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 F365L 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 F365L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.