H401Y

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Histidine → Tyrosine at position 401 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type H401 — ionic bond to D367

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DynaMut2 mutant · H401Y

Mutant Y401 — ionic bond to D367 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost9 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	D367	—	Lost
Hydrogen bond	—	G257	Gained
Hydrogen bond	—	I259	Gained
Hydrogen bond	F397	F397	Preserved
Hydrogen bond	G398	—	Lost
Hydrogen bond	P404	P404	Preserved
Polar contact	—	G257	Gained
Polar contact	I259	I259	Preserved
Polar contact	—	D367	Gained
Polar contact	F397	F397	Preserved
Polar contact	G398	G398	Preserved
Polar contact	W399	W399	Preserved
Polar contact	—	E403	Gained
Polar contact	P404	P404	Preserved
Aromatic / π	F397	F397	Preserved
Van der Waals	—	D367	Gained
Van der Waals	F397	F397	Preserved
Van der Waals	—	W399	Gained
Van der Waals	E403	—	Lost
Van der Waals	P404	—	Lost
Hydrophobic	—	I259	Gained
Hydrophobic	—	D367	Gained
Hydrophobic	F397	F397	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

1.13kcal/mol

Stabilising — moderate

AlphaMissense

0.747

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00082%

cDNA changec.1201C>T

ClinVar accessionVCV002134530

Last evaluated2023/08/30 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — H401Y Variant Card

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

Histidine → Tyrosine at position 401. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.747, DynaMut2 ΔΔG +1.13 kcal/mol (stabilising).

Identity

Field	Value
Variant	H401Y (p.Histidine401Tyrosine)
DNA change	c.1201C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002134530
Amino acid change	Histidine (H) → Tyrosine (Y)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 401	81.94 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 401 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 401 sits in a transmembrane helix (Transmembrane helix 4). 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 titratable basic (histidine — imidazole); the mutant is aromatic with hydroxyl (tyrosine — 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	0.7471
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	1.13 (Stabilising)
Job ID	178092121347
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092121347

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/08/30 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	H401Y 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.13 < 2 kcal/mol (fold intact) + AlphaMissense 0.747 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|=1.13 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.747. 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
H401Y_molstar_viewer.html — interactive 3D viewer (auto-highlights position 401 with ball-and-stick + neighbors within 5Å)
H401Y_variant_card.md — this card (source of truth)
H401Y_variant_card.html — styled printable card
H401Y_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)
H401Y_wildtype_interactions.pse / H401Y_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 H401Y 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 H401Y PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.