T442I

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

Threonine → Isoleucine at position 442 · Transmembrane helix 5 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type T442 — hydrogen bond to S446

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DynaMut2 mutant · T442I

Mutant I442 — hydrogen bond contact to F439 lost

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Bond changes · DynaMut2 interaction analysis

1 lost5 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	F438	F438	Preserved
Hydrogen bond	F439	F439	Preserved
Hydrogen bond	—	L445	Gained
Hydrogen bond	S446	S446	Preserved
Polar contact	F438	F438	Preserved
Polar contact	F439	—	Lost
Polar contact	—	Y444	Gained
Polar contact	L445	L445	Preserved
Polar contact	S446	S446	Preserved
Van der Waals	—	Y444	Gained
Hydrophobic	—	F365	Gained
Hydrophobic	F438	F438	Preserved
Hydrophobic	—	F439	Gained

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

-0.83kcal/mol

Destabilising — mild

AlphaMissense

0.457

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 0.00027%

cDNA changec.1325C>T

ClinVar accessionVCV002793721

Last evaluated2024/03/30 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — T442I Variant Card

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

Threonine → Isoleucine at position 442. Transmembrane helix 5. ClinVar Uncertain significance, AlphaMissense 0.457, DynaMut2 ΔΔG -0.83 kcal/mol (destabilising).

Identity

Field	Value
Variant	T442I (p.Threonine442Isoleucine)
DNA change	c.1325C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002793721
Amino acid change	Threonine (T) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 442	87.69 — well-folded
Domain	Transmembrane helix 5
Position context	Inside Transmembrane helix 5 · position 442 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 442 sits in a transmembrane helix (Transmembrane helix 5). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is small polar (threonine — hydroxyl); the mutant is medium hydrophobic (isoleucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4566
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.83 (Destabilising)
Job ID	178094718055
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094718055

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/03/30 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	T442I 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|=0.83 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.83 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.457. 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
T442I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 442 with ball-and-stick + neighbors within 5Å)
T442I_variant_card.md — this card (source of truth)
T442I_variant_card.html — styled printable card
T442I_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)
T442I_wildtype_interactions.pse / T442I_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 T442I 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 T442I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.