H109Y

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Histidine → Tyrosine at position 109 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

His→Tyr p109 N-term AM=0.07 ddg=+1.1 pLDDT=92. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type H109 — hydrogen bond to E105

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DynaMut2 mutant · H109Y

Mutant Y109 — hydrogen bond to V106 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E105	E105	Preserved
Hydrogen bond	V106	V106	Preserved
Hydrogen bond	Q112	Q112	Preserved
Hydrogen bond	L113	L113	Preserved
Polar contact	F88	—	Lost
Polar contact	E105	E105	Preserved
Polar contact	V106	V106	Preserved
Polar contact	L111	—	Lost
Polar contact	Q112	Q112	Preserved
Polar contact	L113	L113	Preserved
Aromatic / π	F88	F88	Preserved
Van der Waals	F88	—	Lost
Van der Waals	—	V106	Gained
Van der Waals	Q112	—	Lost
Van der Waals	L113	—	Lost
Hydrophobic	F88	F88	Preserved
Hydrophobic	—	L113	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

1.10kcal/mol

Stabilising — moderate

AlphaMissense

0.073

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 0.0073%

cDNA changec.325C>T

ClinVar accessionVCV000166570

Last evaluated2025/10/14 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: LYS108 (2.5 Å — same K108 as G107E neighbor!), TYR110 (2.5 Å — adjacent existing Y!), VAL106 (3.6 Å — same V106 as G107E neighbor). Same G107-K108-H109 cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

aromatic substitution stabilising

Position in the protein

N-terminal cytoplasmic domain

Druggability Assessment

Cat 4 stabilising — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

H109Y + G107E in same K108 cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the H109Y 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 H109Y PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A