A134V

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Alanine → Valine at position 134 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A134 — hydrogen bond to G137

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DynaMut2 mutant · A134V

Mutant V134 — energy-minimized; 3 new contacts formed

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L130	L130	Preserved
Hydrogen bond	V131	V131	Preserved
Hydrogen bond	G137	G137	Preserved
Hydrogen bond	R177	R177	Preserved
Polar contact	L130	L130	Preserved
Polar contact	V131	V131	Preserved
Polar contact	Q136	Q136	Preserved
Polar contact	G137	G137	Preserved
Polar contact	R177	R177	Preserved
Van der Waals	—	V131	Gained
Van der Waals	—	L166	Gained
Hydrophobic	—	V131	Gained
Hydrophobic	A141	A141	Preserved
Hydrophobic	V142	V142	Preserved
Hydrophobic	L145	L145	Preserved
Hydrophobic	L166	L166	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

-0.92kcal/mol

Destabilising — mild

AlphaMissense

0.622

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0025%

cDNA changec.401C>T

ClinVar accessionVCV001027526

Last evaluated2025/08/14 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A134V Variant Card

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

Alanine → Valine at position 134. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.622, DynaMut2 ΔΔG -0.92 kcal/mol (destabilising).

Identity

Field	Value
Variant	A134V (p.Alanine134Valine)
DNA change	c.401C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001027526
Amino acid change	Alanine (A) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 134	90.94 — well-folded
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 134 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small/hydrophobic (alanine — methyl sidechain); 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	0.6218
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.92 (Destabilising)
Job ID	178092130561
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092130561

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/08/14 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A134V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.92 < 2 kcal/mol (fold intact) + AlphaMissense 0.622 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|=0.92 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.622. 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
A134V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 134 with ball-and-stick + neighbors within 5Å)
A134V_variant_card.md — this card (source of truth)
A134V_variant_card.html — styled printable card
A134V_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)
A134V_wildtype_interactions.pse / A134V_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 A134V 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 A134V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.