V779L

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Valine → Leucine at position 779 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V779 — hydrogen bond to I802

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DynaMut2 mutant · V779L

Mutant L779 — hydrogen bond to R703 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost4 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R703	—	Lost
Hydrogen bond	D801	D801	Preserved
Hydrogen bond	I802	I802	Preserved
Polar contact	D801	D801	Preserved
Polar contact	I802	I802	Preserved
Carbonyl	—	D801	Gained
Van der Waals	G702	—	Lost
Van der Waals	—	F704	Gained
Van der Waals	—	D801	Gained
Hydrophobic	—	F704	Gained
Hydrophobic	I777	I777	Preserved
Hydrophobic	M781	—	Lost
Hydrophobic	L804	L804	Preserved
Hydrophobic	I823	I823	Preserved
Hydrophobic	F825	F825	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

-0.60kcal/mol

Destabilising — mild

AlphaMissense

0.418

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00050%

cDNA changec.2335G>T

ClinVar accessionVCV002189687

Last evaluated2024/03/25 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — V779L Variant Card

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

Valine → Leucine at position 779. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.418, DynaMut2 ΔΔG -0.60 kcal/mol (destabilising).

Identity

Field	Value
Variant	V779L (p.Valine779Leucine)
DNA change	c.2335G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002189687
Amino acid change	Valine (V) → Leucine (L)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 779	90.12 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 779 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 779 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 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	0.4185
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.6 (Destabilising)
Job ID	178094699393
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094699393

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/03/25 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	V779L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Cataract 41
Wolfram-like syndrome
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.60 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.60 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.418. 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
V779L_molstar_viewer.html — interactive 3D viewer (auto-highlights position 779 with ball-and-stick + neighbors within 5Å)
V779L_variant_card.md — this card (source of truth)
V779L_variant_card.html — styled printable card
V779L_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)
V779L_wildtype_interactions.pse / V779L_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 V779L 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 V779L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.