G702S
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialA conserved glycine inside a tight lumenal hairpin gives way to serine — the loss of glycine's torsional freedom is the entire mechanism, and the neighboring Arg703 hydrogen-bond partner is the structural casualty.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | V779 | Gained |
| Hydrogen bond | — | G780 | Gained |
| Hydrogen bond | — | M781 | Gained |
| Hydrogen bond | L822 | L822 | Preserved |
| Hydrogen bond | I823 | I823 | Preserved |
| Polar contact | — | V779 | Gained |
| Polar contact | — | G780 | Gained |
| Polar contact | — | M781 | Gained |
| Polar contact | — | L822 | Gained |
| Polar contact | I823 | I823 | Preserved |
| Carbonyl | — | L822 | Gained |
| Van der Waals | V779 | — | Lost |
| Van der Waals | — | M781 | Gained |
| Van der Waals | — | L822 | 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 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 South Asian: AF 0.0099% (9 of 91,076 alleles), 4.4x 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. |
|---|---|---|---|---|
| South Asian | 0.0099% | 9 / 91,076 | 0 | ~1 in 5060 |
| Admixed American | 0.0050% | 3 / 59,994 | 0 | ~1 in 10000 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,600 | 0 | — |
| Remaining individuals | 0.0032% | 2 / 62,464 | 0 | ~1 in 15620 |
| European (non-Finnish) | 0.0017% | 20 / 1,179,820 | 0 | ~1 in 29500 |
| African / African American · under-sampled | 0.0013% | 1 / 74,910 | 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
G702 is wedged into a dense lumenal core. Its immediate covalent neighbors Arg703 (2.44 Angstrom) and Thr701 (2.45 Angstrom) flank it; the through-space contacts read like a packed hydrophobic-polar cluster — Val779 (3.50 Angstrom), Gly780 (3.54 Angstrom), Pro782 (3.76 Angstrom), Ile823 (3.89 Angstrom), Met781 (4.06 Angstrom), Phe825 (4.42 Angstrom). The Gly702-Gly780 pairing across 3.5 Angstrom is structurally interesting: two glycines in close apposition usually means a turn or hairpin that requires both backbones to adopt unusual phi/psi angles unavailable to other residues.
Replacing G702 with serine eliminates that geometric license. Serine has a beta-carbon and a hydroxyl, both compatible with standard Ramachandran space but incompatible with the disallowed-region phi/psi values that glycine populates here. The local backbone is forced to find a new conformation, and because Arg703 is the immediate downstream neighbor, the rearrangement carries Arg703's guanidinium with it — almost certainly displacing whatever salt bridge or hydrogen bond Arg703 contributes to the lumenal contact network with Pro782, Met781, or the Phe825 ring.
DynaMut2 returns DeltaDeltaG = -1.25 kcal/mol — destabilising and on the upper edge of the mild bucket. AlphaMissense 0.944 reads this as clearly pathogenic. The combination is consistent with a residue whose evolutionary indispensability is purely geometric: glycine is conserved at 702 not for any chemical contribution it makes but for the backbone freedom it provides. Any other residue, even one as conservative as serine, breaks the hairpin.
Clinically, G702S is documented in Wolfram syndrome 1 and optic atrophy — phenotypes that fit a lumenal-domain perturbation interfering with the ATF6 unfolded protein response axis. The fold survives; the function does not.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the G702S 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.