G736S
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialA glycine-to-serine substitution at a lumenal turn that brings a free thiol (Cys733) and a histidine (His766) into structural register — backbone freedom is lost where wolframin requires it, and the polar cluster reorganizes.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R732 | R732 | Preserved |
| Polar contact | R732 | R732 | Preserved |
| Polar contact | H766 | H766 | Preserved |
| Polar contact | — | I767 | Gained |
| Carbonyl | H766 | — | Lost |
| Van der Waals | H766 | H766 | 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 Hearing loss, inheritance unstated (inheritance not specified); 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.
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Monogenic hearing loss
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 East Asian: AF 0.0089% (4 of 44,866 alleles), 2.8x 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. |
|---|---|---|---|---|
| East Asian | 0.0089% | 4 / 44,866 | 0 | ~1 in 5610 |
| European (non-Finnish) | 0.0037% | 44 / 1,179,916 | 0 | ~1 in 13410 |
| Remaining individuals | 0.0032% | 2 / 62,452 | 0 | ~1 in 15610 |
| Admixed American · under-sampled | 0.0017% | 1 / 59,974 | 0 | — |
| South Asian · under-sampled | 0.0011% | 1 / 91,068 | 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
G736 is wedged between Glu737 (2.41 Angstrom) and Tyr735 (2.47 Angstrom), with a through-space contact cluster reading Arg732 (3.07 Angstrom), His766 (3.29 Angstrom), Ile767 (4.09 Angstrom), Cys733 (4.88 Angstrom), and Leu734 (5.00 Angstrom). The local geometry is structurally complex: a tyrosine-glycine-glutamate sequence sandwiched between an arginine three residues upstream, a histidine six residues downstream by sequence but within 3.3 Angstrom by space, and a free cysteine within 5 Angstrom.
The wild-type glycine at 736 is doing exactly what glycines do best — providing the backbone flexibility that brings Arg732 (3.07 Angstrom), the Tyr735 phenol, and His766 (3.29 Angstrom) into close polar register. The Tyr735 hydroxyl, the Arg732 guanidinium, the Glu737 carboxylate, and the His766 imidazole are all polar-functional groups that the local geometry stages into a hydrogen-bond / electrostatic network. Glycine's job here is to allow the backbone turn that makes this network possible.
Replacing G736 with serine removes the disallowed-region phi/psi freedom and forces the chain into standard geometry. The Tyr735-Arg732-His766 register opens up; the Glu737 contact shifts; the local polar network — which is almost certainly part of the lumenal-domain functional surface — is degraded. DynaMut2's DeltaDeltaG of -1.1 kcal/mol captures the moderate destabilization; AlphaMissense at 0.862 confirms the position is evolutionarily constrained.
The Cys733 at 4.88 Angstrom is a secondary concern. In the wild-type configuration, the geometry holds Cys733 in a defined position relative to the polar cluster. The G736S-induced rearrangement may expose Cys733's thiol to a different local environment, potentially raising disulfide-formation risk in the oxidizing ER lumen. This is inference, not observation, but the structural signature supports it.
ClinVar links G736S to Wolfram syndrome 1, Wolfram-like syndrome, and monogenic hearing loss — phenotypic breadth consistent with partial loss of lumenal-domain function.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the G736S 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.