A179T

Category 2 — Moderately DestabilizingUncertain significanceCytoplasmic · predictedSource card

Alanine → Threonine at position 179 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A179 — hydrogen bond to M183

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DynaMut2 mutant · A179T

Mutant T179 — van der waals to M183 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	A175	A175	Preserved
Hydrogen bond	V176	V176	Preserved
Hydrogen bond	M183	M183	Preserved
Polar contact	A175	A175	Preserved
Polar contact	V176	V176	Preserved
Polar contact	R177	R177	Preserved
Polar contact	L181	L181	Preserved
Polar contact	V182	V182	Preserved
Polar contact	M183	M183	Preserved
Polar contact	—	L381	Gained
Polar contact	—	E385	Gained
Van der Waals	R177	R177	Preserved
Van der Waals	L181	L181	Preserved
Van der Waals	M183	—	Lost
Van der Waals	—	L381	Gained
Hydrophobic	L381	L381	Preserved
Hydrophobic	F384	F384	Preserved
Hydrophobic	E385	—	Lost

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

-2.09kcal/mol

Destabilising — large

AlphaMissense

0.934

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance/Uncertain risk allele

Review statuscriteria provided, multiple submitters, no conflicts

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%

cDNA changec.535G>A

ClinVar accessionVCV000229647

Last evaluated2026/02/23 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A179T Variant Card

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

Alanine → Threonine at position 179. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.934, DynaMut2 ΔΔG -2.09 kcal/mol (destabilising).

Identity

Field	Value
Variant	A179T (p.Alanine179Threonine)
DNA change	c.535G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000229647
Amino acid change	Alanine (A) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 179	88.56 — 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 179 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	0.9343
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.09 (Destabilising)
Job ID	178092143728
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092143728

Clinical Evidence

Field	Value
Classification	Uncertain significance/Uncertain risk allele
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/02/23 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A179T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.09 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
A179T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 179 with ball-and-stick + neighbors within 5Å)
A179T_variant_card.md — this card (source of truth)
A179T_variant_card.html — styled printable card
A179T_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)
A179T_wildtype_interactions.pse / A179T_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 A179T 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 A179T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.