A134T

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

Alanine → Threonine 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 · A134T

Mutant T134 — hydrophobic to L145 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost4 gained11 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	—	L166	Gained
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	—	V142	Gained
Polar contact	R177	R177	Preserved
Van der Waals	—	V131	Gained
Hydrophobic	—	V131	Gained
Hydrophobic	A141	—	Lost
Hydrophobic	V142	—	Lost
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

-1.73kcal/mol

Destabilising — moderate

AlphaMissense

0.411

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 conditionsMonogenic diabetes; Hereditary ataxia; WFS1-Related Spectrum Disorders; Wolfram syndrome 1; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome

Population frequency (gnomAD v4)Low frequency · AF 0.036%

cDNA changec.400G>A

ClinVar accessionVCV000215410

Last evaluated2025/10/14 00:00

Observed in the general population.

Full Variant Card

WFS1 Wolframin — A134T Variant Card

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

Alanine → Threonine at position 134. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.411, DynaMut2 ΔΔG -1.73 kcal/mol (destabilising).

Identity

Field	Value
Variant	A134T (p.Alanine134Threonine)
DNA change	c.400G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000215410
Amino acid change	Alanine (A) → Threonine (T)

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 polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4113
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.73 (Destabilising)
Job ID	178094703577
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094703577

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/10/14 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A134T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Monogenic diabetes
Hereditary ataxia
WFS1-Related Spectrum Disorders
Wolfram syndrome 1
Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
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|=1.73 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.73 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.411. 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
A134T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 134 with ball-and-stick + neighbors within 5Å)
A134T_variant_card.md — this card (source of truth)
A134T_variant_card.html — styled printable card
A134T_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)
A134T_wildtype_interactions.pse / A134T_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 A134T 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 A134T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.