S446N

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Serine → Asparagine at position 446 · Transmembrane helix 5 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type S446 — hydrogen bond to S443

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DynaMut2 mutant · S446N

Mutant N446 — hydrogen bond contact to S443 lost

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Bond changes · DynaMut2 interaction analysis

0 lost4 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T442	T442	Preserved
Hydrogen bond	S443	S443	Preserved
Polar contact	F365	F365	Preserved
Polar contact	—	S368	Gained
Polar contact	T442	T442	Preserved
Polar contact	S443	S443	Preserved
Polar contact	Y444	Y444	Preserved
Van der Waals	—	F365	Gained
Van der Waals	—	Y444	Gained
Hydrophobic	—	F365	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

0.17kcal/mol

Stabilising — mild

AlphaMissense

0.773

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1337G>A

ClinVar accessionVCV003981552

Last evaluated2025/06/07 00:00

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

Full Variant Card

WFS1 Wolframin — S446N Variant Card

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

Serine → Asparagine at position 446. Transmembrane helix 5. ClinVar Uncertain significance, AlphaMissense 0.773, DynaMut2 ΔΔG +0.17 kcal/mol (stabilising).

Identity

Field	Value
Variant	S446N (p.Serine446Asparagine)
DNA change	c.1337G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003981552
Amino acid change	Serine (S) → Asparagine (N)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 446	82.25 — well-folded
Domain	Transmembrane helix 5
Position context	Inside Transmembrane helix 5 · position 446 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 446 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 (serine — hydroxyl); 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	0.7727
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.17 (Stabilising)
Job ID	178092118847
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092118847

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/06/07 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	S446N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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|=0.17 < 2 kcal/mol (fold intact) + AlphaMissense 0.773 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|=0.17 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.773. 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
S446N_molstar_viewer.html — interactive 3D viewer (auto-highlights position 446 with ball-and-stick + neighbors within 5Å)
S446N_variant_card.md — this card (source of truth)
S446N_variant_card.html — styled printable card
S446N_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)
S446N_wildtype_interactions.pse / S446N_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 S446N 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 S446N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.