L377V

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Leucine → Valine at position 377 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type L377 — hydrogen bond to L381

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DynaMut2 mutant · L377V

Mutant V377 — hydrogen bond to M229 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost3 gained15 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M229	M229	Preserved
Hydrogen bond	N373	N373	Preserved
Hydrogen bond	F374	F374	Preserved
Hydrogen bond	L380	L380	Preserved
Hydrogen bond	L381	L381	Preserved
Polar contact	—	M229	Gained
Polar contact	N373	N373	Preserved
Polar contact	F374	F374	Preserved
Polar contact	R375	R375	Preserved
Polar contact	D379	D379	Preserved
Polar contact	L380	L380	Preserved
Polar contact	L381	L381	Preserved
Carbonyl	L380	—	Lost
Van der Waals	—	Y254	Gained
Van der Waals	D379	D379	Preserved
Van der Waals	—	L380	Gained
Hydrophobic	M229	M229	Preserved
Hydrophobic	L233	—	Lost
Hydrophobic	T251	—	Lost
Hydrophobic	Y254	Y254	Preserved
Hydrophobic	L381	L381	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

-1.07kcal/mol

Destabilising — moderate

AlphaMissense

0.341

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.00099%

cDNA changec.1129C>G

ClinVar accessionVCV002195963

Last evaluated2025/10/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — L377V Variant Card

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

Leucine → Valine at position 377. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.341, DynaMut2 ΔΔG -1.07 kcal/mol (destabilising).

Identity

Field	Value
Variant	L377V (p.Leucine377Valine)
DNA change	c.1129C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002195963
Amino acid change	Leucine (L) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 377	84.00 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 377 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 377 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 medium hydrophobic (leucine — branched); the mutant is small hydrophobic (valine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3409
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.07 (Destabilising)
Job ID	178094712837
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094712837

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/10/15 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	L377V 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.07 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.07 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.341. 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
L377V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 377 with ball-and-stick + neighbors within 5Å)
L377V_variant_card.md — this card (source of truth)
L377V_variant_card.html — styled printable card
L377V_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)
L377V_wildtype_interactions.pse / L377V_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 L377V 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 L377V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.