E737K
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 737 in lumenal domain. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.18 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.10 (neutral). Same E737 contacted by G736R, G736S, C765R.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | H766 | — | Lost |
| Hydrogen bond | H766 | H766 | Preserved |
| Hydrogen bond | K769 | — | Lost |
| Polar contact | C765 | — | Lost |
| Polar contact | H766 | H766 | Preserved |
| Carbonyl | C765 | — | Lost |
| Van der Waals | C765 | — | Lost |
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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). 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 Spectrum Disorders
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in East Asian: AF 2.89% (1296 of 44,860 alleles), 31.0x the global figure. The global AF describes the general population, not the at-risk group.
26 homozygotes reported in gnomAD v4 (26 East Asian). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| East Asian | 2.89% | 1,296 / 44,860 | 26 | ~1 in 17 |
| Ashkenazi Jewish | 0.182% | 54 / 29,590 | 0 | ~1 in 270 |
| Remaining individuals | 0.061% | 38 / 62,480 | 0 | ~1 in 820 |
| Middle Eastern | 0.033% | 2 / 6,062 | 0 | ~1 in 1520 |
| Admixed American | 0.013% | 8 / 59,990 | 0 | ~1 in 3750 |
| European (non-Finnish) | 0.0083% | 98 / 1,179,896 | 0 | ~1 in 6020 |
| South Asian | 0.0077% | 7 / 91,066 | 0 | ~1 in 6500 |
| African / African American · under-sampled | 0.0013% | 1 / 75,044 | 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
Position 737 — the E737 hub residue itself. Neighbors: ALA738 (2.4 Å), GLY736 (2.5 Å — G736R/G736S!), HIS766 (3.8 Å — same H766 as C765R neighbor).
E737K is the variant AT the hub position that G736R, G736S, and C765R all contact. Charge-flip disrupts the entire microregion's electrostatic geometry. Three convergent Atlas variants point at E737 from their neighbor analyses; now we have the variant at the hub itself.
AM 0.18 under-call; WFS1 spectrum confirms.
Druggability Assessment
Mechanism: charge-flip at E737 hub. Therapeutic: this is the second hub residue in the Atlas (with E431). Drug discovery targets E737 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the E737K 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.