A307V

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

Alanine → Valine at position 307 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A307 — hydrogen bond to G311

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DynaMut2 mutant · A307V

Mutant V307 — polar contact contact to L303 lost

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L303	L303	Preserved
Hydrogen bond	I304	I304	Preserved
Hydrogen bond	G311	G311	Preserved
Polar contact	L303	L303	Preserved
Polar contact	I304	I304	Preserved
Polar contact	—	A310	Gained
Polar contact	G311	G311	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

-0.81kcal/mol

Destabilising — mild

AlphaMissense

0.350

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 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 0.00025%

cDNA changec.920C>T

ClinVar accessionVCV001057020

Last evaluated2025/01/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A307V Variant Card

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

Alanine → Valine at position 307. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.350, DynaMut2 ΔΔG -0.81 kcal/mol (destabilising).

Identity

Field	Value
Variant	A307V (p.Alanine307Valine)
DNA change	c.920C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001057020
Amino acid change	Alanine (A) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 307	59.72 — confident
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 307 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	0.3500
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.81 (Destabilising)
Job ID	178094702783
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094702783

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/01/15 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A307V 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.81 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.350. 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
A307V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 307 with ball-and-stick + neighbors within 5Å)
A307V_variant_card.md — this card (source of truth)
A307V_variant_card.html — styled printable card
A307V_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)
A307V_wildtype_interactions.pse / A307V_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 A307V 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 A307V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.