H407Y

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Histidine → Tyrosine at position 407 · TM3 (402-422), helical transmembrane · WFS1 (Wolframin)

His→Tyr p407 TM3 AM=0.10 ddg=+1.05 pLDDT=90. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type H407 — ionic bond to E403

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DynaMut2 mutant · H407Y

Mutant Y407 — ionic bond to E403 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost5 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E403	—	Lost
Hydrogen bond	E403	E403	Preserved
Hydrogen bond	—	L410	Gained
Hydrogen bond	S411	S411	Preserved
Hydrogen bond	—	K634	Gained
Polar contact	E403	E403	Preserved
Polar contact	P404	P404	Preserved
Polar contact	—	L410	Gained
Polar contact	S411	S411	Preserved
Van der Waals	C360	—	Lost
Van der Waals	E403	E403	Preserved
Hydrophobic	—	E403	Gained
Hydrophobic	V633	—	Lost
Hydrophobic	—	K634	Gained
Hydrophobic	L637	L637	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

1.05kcal/mol

Stabilising — moderate

AlphaMissense

0.100

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0011%

cDNA changec.1219C>T

ClinVar accessionVCV000166583

Last evaluated2025/12/10 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: PHE408 (2.5 Å — F408 TM3-TM7 interface!), ALA406 (2.5 Å), PRO404 (3.8 Å). Aromatic-rich TM3 environment near F408 cross-helix hub. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

aromatic substitution stabilising

Position in the protein

TM3 (402-422)

Druggability Assessment

Cat 4 stabilising — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

Why this matters

TM3 F408 interface variant.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the H407Y 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 H407Y PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane402–422 · Helical