F775V

Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorial

Phenylalanine → Valine at position 775 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Phenylalanine → Valine at position 775. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.941, ΔΔG -1.57 (substantial destabilization). Aromatic loss in a cross-domain contact position.

Interactive 3D Structure

Wild-type reference

Wild-type F775 — hydrogen bond to A806

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DynaMut2 mutant · F775V

Mutant V775 — hydrogen bond to R708 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost2 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R708	R708	Preserved
Hydrogen bond	R805	R805	Preserved
Hydrogen bond	A806	A806	Preserved
Polar contact	R708	R708	Preserved
Polar contact	R805	R805	Preserved
Polar contact	A806	A806	Preserved
Carbonyl	R708	R708	Preserved
Van der Waals	R708	R708	Preserved
Van der Waals	Y773	—	Lost
Van der Waals	—	A806	Gained
Hydrophobic	V707	V707	Preserved
Hydrophobic	V709	V709	Preserved
Hydrophobic	Y773	—	Lost
Hydrophobic	—	I777	Gained
Hydrophobic	A806	A806	Preserved
Hydrophobic	K811	—	Lost
Hydrophobic	L814	L814	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

-1.57kcal/mol

Destabilising — moderate

AlphaMissense

0.941

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsWolfram syndrome 1; Inborn genetic diseases

InheritanceWolfram syndrome 1 documented.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2323T>G

ClinVar accessionVCV000166605

Last evaluated2025/03/23 00:00

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

Structural Context

Position 775 sits in the lumenal domain. Neighbors: GLU776 (2.4 Å — partner of R708 salt-bridge), LYS774 (2.5 Å), ARG708 (3.3 Å — direct R708 contact!), ALA806 (3.7 Å — partner of A806P).

The wild-type phenylalanine at 775 likely participates in the R708-E776 salt-bridge geometry through cation-π interaction between F775's ring and R708's guanidinium. Replacing F775 with valine eliminates this cation-π contribution and reduces the aromatic packing supporting the R708-E776 salt bridge.

The |ΔΔG| of 1.57 reflects substantial fold cost. AlphaMissense 0.941 + Wolfram 1 confirm severe consequence. F775V joins R708L, R708C, A806P as multi-variant convergence on the 775-806 microregion.

Amino-acid chemistry

Phenylalanine (F) → Valine (V) — aromatic hydrophobic replaced by branched aliphatic. Aromatic π-system lost; volume reduced.

Position in the protein

C-terminal lumenal domain · position 775 (pLDDT 94 — high confidence).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 1.57 — fold survives at meaningful cost. AlphaMissense 0.941 + Wolfram 1 confirm severe consequence.

Mechanism: loss of F775 cation-π contribution to R708-E776 salt-bridge geometry. Therapeutic: same R708-E776-F775 microregion (multi-variant target).

Why this matters

F775V is the fourth variant in the 707-708-775-806 microregion (with V707F, R708L, R708C, A806P). Drug discovery here has multi-variant convergence.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F775V 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 F775V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal