I688F

Category 4 — Stable Fold, Function DisruptedLikely pathogenicLumenal · predictedσ-1 candidateEditorial

Isoleucine → Phenylalanine at position 688 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Isoleucine → Phenylalanine at position 688 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.406 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.64 kcal/mol (destabilising).

Interactive 3D Structure

Wild-type reference

Wild-type I688 — hydrogen bond to S691

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DynaMut2 mutant · I688F

Mutant F688 — hydrogen bond contact to R685 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A684	A684	Preserved
Hydrogen bond	R685	—	Lost
Hydrogen bond	S691	S691	Preserved
Polar contact	A684	A684	Preserved
Polar contact	R685	R685	Preserved
Polar contact	T686	T686	Preserved
Polar contact	S691	S691	Preserved
Van der Waals	A684	A684	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

-0.64kcal/mol

Destabilising — mild

AlphaMissense

0.406

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationLikely pathogenic

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1 (AR) documented.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2062A>T

ClinVar accessionVCV003393279

Last evaluated2024/12/19 00:00

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

Structural Context

Position 688 sits adjacent to several R558 microregion-related residues. The AlphaFold model places I688 within 5 Å of LEU689 (2.5 Å), GLN687 (2.5 Å — partner of Q687H Atlas card), ARG685 (3.8 Å — partner of R685P), SER691 (3.9 Å), and ALA684 (4.0 Å — partner of A684T and A684V).

Replacing I688 with phenylalanine adds aromatic volume to a tightly-packed region containing R685, A684, Q687 — all known pathogenic variant positions. The F688 introduction reorganizes the local packing.

The |ΔΔG| of 0.64 reflects fold accommodation. AlphaMissense's 0.406 is below threshold — AM under-call. ClinVar Pathogenic + Wolfram 1 establishes clinical relevance.

Amino-acid chemistry

Isoleucine (I) → Phenylalanine (F) — branched aliphatic hydrophobic replaced by aromatic hydrophobic.

Position in the protein

C-terminal lumenal domain · position 688 in the ER lumen (pLDDT 89).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| = 0.64 — fold survives. AlphaMissense 0.406 below threshold but ClinVar Pathogenic + Wolfram 1.

Mechanism is volume mismatch in the R685-A684-Q687 multi-variant microregion. Therapeutic strategy: same target cluster as A684T, A684V, R685P, Q687H.

Why this matters

I688F joins the dense 684-688 multi-variant cluster — six Atlas variants (A684T, A684V, R685P, Q687H, I688F, plus broader region) converge here.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the I688F 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 I688F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal