Y405H

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

Tyrosine → Histidine at position 405 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type Y405 — hydrogen bond to L409

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DynaMut2 mutant · Y405H

Mutant H405 — hydrogen bond to P533 lost (7 contacts lost)

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Bond changes · DynaMut2 interaction analysis

7 lost2 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V364	—	Lost
Hydrogen bond	—	H401	Gained
Hydrogen bond	L402	L402	Preserved
Hydrogen bond	F408	F408	Preserved
Hydrogen bond	L409	L409	Preserved
Hydrogen bond	P533	—	Lost
Polar contact	V364	—	Lost
Polar contact	—	H401	Gained
Polar contact	L402	L402	Preserved
Polar contact	E403	E403	Preserved
Polar contact	F408	F408	Preserved
Polar contact	L409	L409	Preserved
Van der Waals	L402	L402	Preserved
Van der Waals	E403	E403	Preserved
Van der Waals	V532	—	Lost
Hydrophobic	V364	—	Lost
Hydrophobic	L402	L402	Preserved
Hydrophobic	V532	V532	Preserved
Hydrophobic	P533	—	Lost
Hydrophobic	V536	—	Lost

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

-1.03kcal/mol

Destabilising — moderate

AlphaMissense

0.393

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 conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.00020%

cDNA changec.1213T>C

ClinVar accessionVCV002581797

Last evaluated2026/01/05 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — Y405H Variant Card

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

Tyrosine → Histidine at position 405. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.393, DynaMut2 ΔΔG -1.03 kcal/mol (destabilising).

Identity

Field	Value
Variant	Y405H (p.Tyrosine405Histidine)
DNA change	c.1213T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002581797
Amino acid change	Tyrosine (Y) → Histidine (H)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 405	88.56 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 405 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 405 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 aromatic with hydroxyl (tyrosine — H-bond donor/acceptor); the mutant is titratable basic (histidine — imidazole). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3926
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.03 (Destabilising)
Job ID	178094705213
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094705213

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2026/01/05 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	Y405H 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=1.03 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.03 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.393. 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
Y405H_molstar_viewer.html — interactive 3D viewer (auto-highlights position 405 with ball-and-stick + neighbors within 5Å)
Y405H_variant_card.md — this card (source of truth)
Y405H_variant_card.html — styled printable card
Y405H_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)
Y405H_wildtype_interactions.pse / Y405H_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 Y405H 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 Y405H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.