A126T
Category 3/4 — Most DruggablePathogenic/Likely pathogenicCytoplasmic · predictedEditorialAn alanine-to-threonine substitution inside wolframin's N-terminal cytoplasmic domain — a region that engages ATP6V1A (the V-ATPase regulatory partner) — and sits adjacent to a free cysteine that adds an unwanted disulfide-formation risk.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | L111 | Gained |
| Hydrogen bond | N122 | N122 | Preserved |
| Hydrogen bond | S123 | — | Lost |
| Hydrogen bond | — | W129 | Gained |
| Hydrogen bond | L130 | L130 | Preserved |
| Polar contact | G107 | G107 | Preserved |
| Polar contact | — | L111 | Gained |
| Polar contact | N122 | N122 | Preserved |
| Polar contact | S123 | S123 | Preserved |
| Polar contact | C124 | C124 | Preserved |
| Polar contact | D128 | D128 | Preserved |
| Polar contact | W129 | W129 | Preserved |
| Polar contact | L130 | L130 | Preserved |
| Van der Waals | N122 | — | Lost |
| Van der Waals | C124 | C124 | Preserved |
| Van der Waals | D128 | D128 | Preserved |
| Van der Waals | — | L130 | Gained |
| Hydrophobic | L111 | L111 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 Remaining individuals: AF 0.0032% (2 of 62,174 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. |
|---|---|---|---|---|
| Remaining individuals | 0.0032% | 2 / 62,174 | 0 | ~1 in 15540 |
| European (non-Finnish) | 0.0021% | 25 / 1,176,002 | 0 | ~1 in 23520 |
| Finnish · under-sampled | 0.0016% | 1 / 62,908 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,836 | 0 | — |
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
A126 is held between Thr125 (2.45 Angstrom) and Val127 (2.46 Angstrom), with a tight through-space contact cluster: Asn122 (3.70 Angstrom), Ser123 (3.80 Angstrom), Tyr110 (3.85 Angstrom), Gly107 (4.06 Angstrom), Cys124 (4.22 Angstrom), and Asp128 (4.42 Angstrom). The local environment is polar-rich — three threonines and serines, a tyrosine, an aspartate, an asparagine, and a free cysteine within 4.5 Angstrom. This is a well-organized polar interface, almost certainly part of the ATP6V1A-binding surface.
The wild-type alanine's methyl side chain occupies a single non-polar slot in the polar cluster. Threonine adds a hydroxyl and a beta-branched methyl group. The hydroxyl will look for a hydrogen-bond partner — and Asp128 at 4.42 Angstrom, Asn122 at 3.70 Angstrom, and Ser123 at 3.80 Angstrom all qualify. The result is a forced rearrangement of the local hydrogen-bond network: a contact the wild-type kept open (A126 contributed nothing) is now occupied by the threonine hydroxyl, and the polar partners reorganize accordingly.
The Cys124 contact at 4.22 Angstrom is the second mechanistic concern. Free cytoplasmic cysteines are typically reduced, but local hydrogen-bond reorganization can alter the cysteine's pKa or its local solvation, raising the risk of inappropriate disulfide formation under oxidative stress — and ER-stressed cells in Wolfram syndrome are chronically oxidatively stressed. The threonine introduction at 126 thus has two failure modes: direct disruption of the ATP6V1A-binding surface, and secondary destabilization of Cys124 under cellular stress.
DynaMut2 reports DeltaDeltaG = -1.76 kcal/mol — destabilising and the largest magnitude in this batch. AlphaMissense at 0.878 confirms strong functional constraint. The combination of high pLDDT, sizable destabilization, and functional-surface placement makes A126T mechanistically clear.
Druggability Assessment
Why this matters
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