G437R
Category 3/4 — Most DruggablePathogenic/Likely pathogenicTransmembrane · predictedEditorialA buried glycine in transmembrane helix TM4 is replaced by arginine — the bilayer interior has no business hosting a fully solvated guanidinium, and the helix packing against TM5 collapses.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A433 | A433 | Preserved |
| Hydrogen bond | T440 | T440 | Preserved |
| Hydrogen bond | V441 | V441 | Preserved |
| Polar contact | A433 | A433 | Preserved |
| Polar contact | V434 | V434 | Preserved |
| Polar contact | — | I435 | Gained |
| Polar contact | T440 | T440 | Preserved |
| Polar contact | V441 | V441 | Preserved |
| Van der Waals | — | I435 | 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- 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 European (non-Finnish): AF 0.0040% (45 of 1,112,008 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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0040% | 45 / 1,112,008 | 0 | ~1 in 12360 |
| Remaining individuals | 0.0033% | 2 / 60,390 | 0 | ~1 in 15100 |
| South Asian · under-sampled | 0.0012% | 1 / 86,258 | 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
G437 sits inside TM4's helical core, with Thr436 (2.46 Angstrom) and Phe438 (2.46 Angstrom) as covalent neighbors. The through-space cluster is dense and hydrophobic: Ala433 (3.68 Angstrom), Ser544 (3.80 Angstrom) — note that Ser544 is on a neighboring helix or loop, indicating an inter-helix contact — Val434 (3.83 Angstrom), Thr440 (4.13 Angstrom), Ile435 (4.41 Angstrom), Phe439 (4.42 Angstrom). The wild-type glycine occupies the position where TM4 meets its partner helix; only glycine is small enough to allow that close approach.
Substituting arginine here is a near-worst-case lipid-bilayer mutation. Arginine's guanidinium group carries a delocalized positive charge and requires solvation — typically by water or by phosphate headgroups at the membrane interface. Burying it in the middle of TM4 forces one of two outcomes: either the guanidinium snorkels upward toward the lipid headgroups, dragging the helix backbone out of register, or it remains buried at a substantial desolvation cost (estimated 8-12 kcal/mol for an ionized arginine in low dielectric). Both outcomes destabilize the helix-helix interface that requires glycine's small footprint.
DynaMut2's DeltaDeltaG of -0.59 kcal/mol substantially underestimates the cost, because the energy function does not fully capture transmembrane desolvation. AlphaMissense at 0.935 reads the true severity: G437R is essentially incompatible with normal TM4 packing. The structural prediction is that TM4 either ejects from its native register against TM5 or that the protein fails to insert into the membrane co-translationally — exactly the kind of misfolding that triggers ER retention and ER-associated degradation.
ClinVar records this variant for Wolfram syndrome 1 — consistent with a classical loss-of-function mechanism via misfolding and degradation.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the G437R 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.