V659F

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Valine → Phenylalanine at position 659 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V659 — hydrogen bond to M657

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DynaMut2 mutant · V659F

Mutant F659 — hydrogen bond contact to M657 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M657	M657	Preserved
Hydrogen bond	G695	G695	Preserved
Hydrogen bond	—	E830	Gained
Polar contact	M657	M657	Preserved
Polar contact	N661	N661	Preserved
Polar contact	G695	G695	Preserved
Van der Waals	G695	G695	Preserved
Hydrophobic	—	M657	Gained
Hydrophobic	R697	—	Lost
Hydrophobic	I828	I828	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

-0.41kcal/mol

Destabilising — mild

AlphaMissense

0.598

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 conditionsWolfram syndrome 1

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

cDNA changec.1975G>T

ClinVar accessionVCV003065747

Last evaluated2024/03/29 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — V659F Variant Card

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

Valine → Phenylalanine at position 659. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.598, DynaMut2 ΔΔG -0.41 kcal/mol (destabilising).

Identity

Field	Value
Variant	V659F (p.Valine659Phenylalanine)
DNA change	c.1975G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003065747
Amino acid change	Valine (V) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 659	61.72 — confident
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 659 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 659 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 large aromatic hydrophobic (phenylalanine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5979
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.41 (Destabilising)
Job ID	178092132711
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092132711

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/03/29 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	V659F 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|=0.41 < 2 kcal/mol (fold intact) + AlphaMissense 0.598 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|=0.41 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.598. 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
V659F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 659 with ball-and-stick + neighbors within 5Å)
V659F_variant_card.md — this card (source of truth)
V659F_variant_card.html — styled printable card
V659F_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)
V659F_wildtype_interactions.pse / V659F_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 V659F 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 V659F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.