V176A

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Valine → Alanine at position 176 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type V176 — hydrogen bond to A180

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DynaMut2 mutant · V176A

Mutant A176 — hydrogen bond to L172 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost0 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L172	L172	Preserved
Hydrogen bond	E173	E173	Preserved
Hydrogen bond	A179	A179	Preserved
Hydrogen bond	A180	A180	Preserved
Polar contact	L172	L172	Preserved
Polar contact	E173	E173	Preserved
Polar contact	K178	—	Lost
Polar contact	A179	—	Lost
Polar contact	A180	A180	Preserved
Van der Waals	L172	—	Lost
Van der Waals	A180	A180	Preserved
Hydrophobic	L172	—	Lost
Hydrophobic	T251	—	Lost
Hydrophobic	K252	K252	Preserved
Hydrophobic	A255	A255	Preserved
Hydrophobic	L381	—	Lost
Hydrophobic	L388	—	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

-1.37kcal/mol

Destabilising — moderate

AlphaMissense

0.878

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.0011%

cDNA changec.527T>C

ClinVar accessionVCV001327312

Last evaluated2026/01/02 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — V176A Variant Card

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

Valine → Alanine at position 176. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.878, DynaMut2 ΔΔG -1.37 kcal/mol (destabilising).

Identity

Field	Value
Variant	V176A (p.Valine176Alanine)
DNA change	c.527T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001327312
Amino acid change	Valine (V) → Alanine (A)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 176	88.88 — 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 176 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small hydrophobic (valine — branched); the mutant is small/hydrophobic (alanine — methyl sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8785
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.37 (Destabilising)
Job ID	178092109134
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092109134

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/01/02 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	V176A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=1.37 < 2 kcal/mol (fold intact) + AlphaMissense 0.878 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|=1.37 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.878. 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
V176A_molstar_viewer.html — interactive 3D viewer (auto-highlights position 176 with ball-and-stick + neighbors within 5Å)
V176A_variant_card.md — this card (source of truth)
V176A_variant_card.html — styled printable card
V176A_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)
V176A_wildtype_interactions.pse / V176A_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 V176A 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 V176A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.