I304T

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

Isoleucine → Threonine at position 304 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I304 — hydrogen bond to A307

Fullscreen ↗

DynaMut2 mutant · I304T

Mutant T304 — hydrogen bond to A307 lost (4 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

4 lost1 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K300	K300	Preserved
Hydrogen bond	E301	E301	Preserved
Hydrogen bond	A307	—	Lost
Hydrogen bond	S308	S308	Preserved
Polar contact	K300	K300	Preserved
Polar contact	E301	E301	Preserved
Polar contact	Y302	Y302	Preserved
Polar contact	M306	—	Lost
Polar contact	A307	A307	Preserved
Polar contact	S308	S308	Preserved
Polar contact	—	W613	Gained
Van der Waals	K300	—	Lost
Van der Waals	Y302	Y302	Preserved
Van der Waals	M306	M306	Preserved
Hydrophobic	K300	—	Lost
Hydrophobic	W613	W613	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

-1.43kcal/mol

Destabilising — moderate

AlphaMissense

0.557

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00080%

cDNA changec.911T>C

ClinVar accessionVCV003714794

Last evaluated2024/08/10 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — I304T Variant Card

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

Isoleucine → Threonine at position 304. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.557, DynaMut2 ΔΔG -1.43 kcal/mol (destabilising).

Identity

Field	Value
Variant	I304T (p.Isoleucine304Threonine)
DNA change	c.911T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003714794
Amino acid change	Isoleucine (I) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 304	64.81 — 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 304 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is medium hydrophobic (isoleucine — branched); 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	0.5567
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.43 (Destabilising)
Job ID	178094707408
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094707408

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/08/10 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	I304T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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|=1.43 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.43 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.557. 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
I304T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 304 with ball-and-stick + neighbors within 5Å)
I304T_variant_card.md — this card (source of truth)
I304T_variant_card.html — styled printable card
I304T_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)
I304T_wildtype_interactions.pse / I304T_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 I304T 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 I304T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.