Q687H
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialGlutamine → Histidine at position 687 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications. AlphaMissense 0.996 (near-maximum), DynaMut2 ΔΔG -0.19 kcal/mol (mild destabilising). Strong AM signal in the dense 684-688 cluster.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M683 | M683 | Preserved |
| Hydrogen bond | A684 | A684 | Preserved |
| Hydrogen bond | C690 | — | Lost |
| Hydrogen bond | S691 | S691 | Preserved |
| Hydrogen bond | L833 | L833 | Preserved |
| Polar contact | M683 | M683 | Preserved |
| Polar contact | A684 | A684 | Preserved |
| Polar contact | — | R685 | Gained |
| Polar contact | C690 | C690 | Preserved |
| Polar contact | S691 | S691 | Preserved |
| Polar contact | L833 | L833 | Preserved |
| Van der Waals | — | R685 | Gained |
| Van der Waals | L689 | — | Lost |
| Van der Waals | — | L833 | Gained |
| Hydrophobic | M683 | — | Lost |
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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Submitters conflict on this classification (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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Admixed American: AF 0.0033% (2 of 60,014 alleles), 9.0x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Admixed American | 0.0033% | 2 / 60,014 | 0 | ~1 in 15000 |
| South Asian | 0.0022% | 2 / 91,088 | 0 | ~1 in 22770 |
| European (non-Finnish) | 0.00017% | 2 / 1,179,894 | 0 | ~1 in 294970 |
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 687 sits in the dense 684-688 cluster discussed in the A684T, A684V, R685P, I688F Atlas cards. The AlphaFold model places Q687 within 5 Å of THR686 (2.5 Å), ILE688 (2.5 Å — partner of I688F), LEU833 (3.6 Å — long-range), ALA684 (3.8 Å — partner of A684T, A684V), and MET683 (3.9 Å).
The wild-type glutamine's amide likely H-bonds with the surrounding polar residues in this cluster. Replacing Q687 with histidine introduces an aromatic imidazole with pH-dependent charge. The H-bond geometry changes substantially.
The |ΔΔG| of 0.19 reflects fold accommodation. AlphaMissense's 0.996 (near-maximum) is strong pathogenic signal. ClinVar conflicting classifications suggest context-dependent functional consequence.
Druggability Assessment
Mechanism is amide-to-aromatic substitution disrupting the 684-688 cluster H-bond network. Therapeutic strategy: same cluster target as A684T, A684V, R685P, I688F.
Why this matters
Feed this card to Wolfram Intelligence
Download the Q687H 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.