F374L

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Phenylalanine → Leucine at position 374 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type F374 — hydrogen bond to T378

Fullscreen ↗

DynaMut2 mutant · F374L

Mutant L374 — hydrogen bond to Y254 lost (9 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

9 lost5 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y254	—	Lost
Hydrogen bond	A255	—	Lost
Hydrogen bond	A370	A370	Preserved
Hydrogen bond	W371	W371	Preserved
Hydrogen bond	L377	L377	Preserved
Hydrogen bond	T378	T378	Preserved
Polar contact	—	Y254	Gained
Polar contact	A255	—	Lost
Polar contact	A370	A370	Preserved
Polar contact	W371	W371	Preserved
Polar contact	—	E372	Gained
Polar contact	T376	—	Lost
Polar contact	L377	L377	Preserved
Polar contact	T378	T378	Preserved
Aromatic / π	W371	—	Lost
Aromatic / π	F397	—	Lost
Van der Waals	—	Y254	Gained
Van der Waals	—	E372	Gained
Van der Waals	T376	—	Lost
Van der Waals	—	F397	Gained
Hydrophobic	Y254	Y254	Preserved
Hydrophobic	W371	W371	Preserved
Hydrophobic	T378	T378	Preserved
Hydrophobic	A393	—	Lost
Hydrophobic	E394	—	Lost
Hydrophobic	F397	F397	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

0.03kcal/mol

Stabilising — mild

AlphaMissense

0.983

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 conditionsWolfram syndrome 1

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

cDNA changec.1122C>A

ClinVar accessionVCV001966944

Last evaluated2025/08/10 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — F374L Variant Card

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

Phenylalanine → Leucine at position 374. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.983, DynaMut2 ΔΔG +0.03 kcal/mol (stabilising).

Identity

Field	Value
Variant	F374L (p.Phenylalanine374Leucine)
DNA change	c.1122C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001966944
Amino acid change	Phenylalanine (F) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 374	83.25 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 374 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 374 sits in a transmembrane helix (Transmembrane helix 3). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. 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	0.9833
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.03 (Stabilising)
Job ID	178092092901
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092092901

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/08/10 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	F374L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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|=0.03 < 2 kcal/mol (fold intact) + AlphaMissense 0.983 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|=0.03 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.983. 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
F374L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 374 with ball-and-stick + neighbors within 5Å)
F374L_variant_card.md — this card (source of truth)
F374L_variant_card.html — styled printable card
F374L_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)
F374L_wildtype_interactions.pse / F374L_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 F374L 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 F374L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.