I688F
Category 4 — Stable Fold, Function DisruptedLikely pathogenicLumenal · predictedσ-1 candidateEditorialIsoleucine → 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
Bond changes · DynaMut2 interaction analysis
| 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.
Druggability Assessment
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
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.