V358L

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

Valine → Leucine at position 358 · Transmembrane helix 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V358 — hydrogen bond to L362

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DynaMut2 mutant · V358L

Mutant L358 — hydrogen bond to T361 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost3 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F354	F354	Preserved
Hydrogen bond	I355	I355	Preserved
Hydrogen bond	T361	T361	Preserved
Hydrogen bond	L362	L362	Preserved
Polar contact	F354	F354	Preserved
Polar contact	I355	I355	Preserved
Polar contact	S356	S356	Preserved
Polar contact	C360	—	Lost
Polar contact	T361	T361	Preserved
Polar contact	L362	L362	Preserved
Van der Waals	—	S356	Gained
Van der Waals	L362	L362	Preserved
Van der Waals	—	F439	Gained
Hydrophobic	F354	F354	Preserved
Hydrophobic	L362	—	Lost
Hydrophobic	—	I435	Gained
Hydrophobic	F439	F439	Preserved
Hydrophobic	W540	W540	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

0.52kcal/mol

Stabilising — mild

AlphaMissense

0.343

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; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Wolfram syndrome 1; Type 2 diabetes mellitus; Wolfram-like syndrome

Population frequency (gnomAD v4)Ultra-rare · AF 0.0017%

cDNA changec.1072G>C

ClinVar accessionVCV001195529

Last evaluated2025/11/26 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — V358L Variant Card

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

Valine → Leucine at position 358. Transmembrane helix 2. ClinVar Uncertain significance, AlphaMissense 0.343, DynaMut2 ΔΔG +0.52 kcal/mol (stabilising).

Identity

Field	Value
Variant	V358L (p.Valine358Leucine)
DNA change	c.1072G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001195529
Amino acid change	Valine (V) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 358	91.94 — well-folded
Domain	Transmembrane helix 2
Position context	Inside Transmembrane helix 2 · position 358 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 358 sits in a transmembrane helix (Transmembrane helix 2). 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 small hydrophobic (valine — branched); 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	0.3434
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.52 (Stabilising)
Job ID	178094708536
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094708536

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/11/26 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	V358L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases
Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
Wolfram syndrome 1
Type 2 diabetes mellitus
Wolfram-like syndrome

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|=0.52 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.52 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.343. 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
V358L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 358 with ball-and-stick + neighbors within 5Å)
V358L_variant_card.md — this card (source of truth)
V358L_variant_card.html — styled printable card
V358L_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)
V358L_wildtype_interactions.pse / V358L_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 V358L 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 V358L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.