I359N

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Isoleucine → Asparagine at position 359 · Transmembrane helix 2 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I359 — hydrogen bond to K363

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DynaMut2 mutant · I359N

Mutant N359 — hydrogen bond to I355 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I355	I355	Preserved
Hydrogen bond	L362	L362	Preserved
Hydrogen bond	K363	K363	Preserved
Polar contact	I355	I355	Preserved
Polar contact	S356	S356	Preserved
Polar contact	T361	—	Lost
Polar contact	L362	—	Lost
Polar contact	K363	K363	Preserved
Polar contact	—	V633	Gained
Van der Waals	T361	—	Lost
Van der Waals	V633	V633	Preserved
Hydrophobic	I355	—	Lost
Hydrophobic	V633	V633	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

-0.62kcal/mol

Destabilising — mild

AlphaMissense

0.967

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

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1076T>A

ClinVar accessionVCV001318136

Last evaluated2024/02/06 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Full Variant Card

WFS1 Wolframin — I359N Variant Card

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

Isoleucine → Asparagine at position 359. Transmembrane helix 2. ClinVar Uncertain significance, AlphaMissense 0.967, DynaMut2 ΔΔG -0.62 kcal/mol (destabilising).

Identity

Field	Value
Variant	I359N (p.Isoleucine359Asparagine)
DNA change	c.1076T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001318136
Amino acid change	Isoleucine (I) → Asparagine (N)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 359	88.62 — well-folded
Domain	Transmembrane helix 2
Position context	Inside Transmembrane helix 2 · position 359 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 359 sits in a transmembrane helix (Transmembrane helix 2). 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 medium hydrophobic (isoleucine — branched); the mutant is polar amide (asparagine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9670
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.62 (Destabilising)
Job ID	178092097384
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092097384

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/02/06 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	I359N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.62 < 2 kcal/mol (fold intact) + AlphaMissense 0.967 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|=0.62 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.967. 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
I359N_molstar_viewer.html — interactive 3D viewer (auto-highlights position 359 with ball-and-stick + neighbors within 5Å)
I359N_variant_card.md — this card (source of truth)
I359N_variant_card.html — styled printable card
I359N_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)
I359N_wildtype_interactions.pse / I359N_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 I359N 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 I359N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.