A684V
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialA conservative alanine-to-valine swap in the lumenal domain with an outsized clinical footprint — UniProt annotation explicitly notes greatly reduced protein expression, locating A684V mechanistically downstream of an ER-quality-control checkpoint.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Van der Waals | N682 | N682 | Preserved |
| Van der Waals | I688 | I688 | Preserved |
| Hydrophobic | — | N682 | Gained |
| Hydrophobic | — | I688 | 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
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 Pathogenic/Likely pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Hearing loss, inheritance unstated (inheritance not specified); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Optic atrophy / optic neuropathy (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder; WFS1 Spectrum Disorder
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss; Autosomal dominant nonsyndromic hearing loss 6
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00027% (3 of 1,111,910 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| Finnish · under-sampled | 0.0019% | 1 / 52,226 | 0 | — |
| European (non-Finnish) | 0.00027% | 3 / 1,111,910 | 0 | ~1 in 185320 |
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
A684 is held tightly between Met683 (2.46 Angstrom) and Arg685 (2.47 Angstrom), with through-space neighbors Gln687 (3.99 Angstrom), Asn682 (4.00 Angstrom), and Thr686 (4.43 Angstrom). The contact set is small and almost entirely polar — Met683's thioether sulfur, Arg685's guanidinium, Gln687's amide, Asn682's amide, and Thr686's hydroxyl. The wild-type alanine's compact methyl side chain fits neatly into this polar surround without participating in the hydrogen-bond network that the surrounding residues maintain.
Valine introduces an isopropyl side chain — beta-branched, sterically larger, and chemically hydrophobic in a position the protein has evolved to keep small. The most likely structural consequence is not catastrophic packing failure but a subtle reorganization: the isopropyl group displaces one of the polar contacts (likely the Thr686 hydroxyl at 4.43 Angstrom, the most peripheral), and the local hydrogen-bond network rearranges to compensate. This is consistent with DynaMut2's mild DeltaDeltaG of -0.81 kcal/mol — the fold is intact but the contact register is shifted.
The critical functional data does not come from the energy function, however. The UniProt natural-variant annotation for A684V records greatly reduced protein expression compared to wild-type — a direct experimental observation. This locates the mechanism downstream of folding per se and inside the ER's quality-control machinery: A684V folds well enough by computational metrics, but the cell flags it as substandard and degrades it via ERAD (ER-associated degradation). The mild backbone perturbation is sufficient to expose a degron or to delay maturation enough that the protein is removed before reaching the membrane in productive form.
AlphaMissense scores this 0.886 — clearly pathogenic, consistent with the experimental expression data. ClinVar links A684V to an unusually broad phenotypic spectrum: Wolfram syndrome 1, Wolfram-like syndrome, optic atrophy, autosomal dominant nonsyndromic hearing loss 6, and the WFS1 spectrum disorders. This breadth implies that residual A684V wolframin produces graded dysfunction depending on tissue and modifier background.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the A684V 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.