V503G
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialValine → Glycine at position 503 inside TM6. ClinVar Pathogenic for DFNA6 hearing loss. AlphaMissense 0.38 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.88 kcal/mol — close to Cat 2 boundary. Cavity creation in dense TM6 multi-variant cluster.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L484 | — | Lost |
| Hydrogen bond | L506 | L506 | Preserved |
| Hydrogen bond | L507 | L507 | Preserved |
| Polar contact | L484 | — | Lost |
| Polar contact | C505 | C505 | Preserved |
| Polar contact | L506 | L506 | Preserved |
| Polar contact | L507 | L507 | Preserved |
| Van der Waals | — | C505 | Gained |
| Van der Waals | L506 | — | Lost |
| Hydrophobic | L468 | — | Lost |
| Hydrophobic | F488 | — | 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
- 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 Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Hearing loss, inheritance unstated (inheritance not specified). 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.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Auditory neuropathy
- 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 0.048% (19 of 39,694 alleles), 34.9x 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 | 0.048% | 19 / 39,694 | 0 | ~1 in 1040 |
| Remaining individuals · under-sampled | 0.0017% | 1 / 60,366 | 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 503 sits in TM6, immediately upstream of P504 (P504L Atlas card) and C505 (C505Y, Y508C Atlas region). Neighbors: SER502 (2.5 Å), PRO504 (2.5 Å), CYS505 (4.3 Å). The TM6 mid-helix region is now extensively characterized in the Atlas — V503G, P504L, C505Y, Y508C all converge here.
Replacing V503 with glycine eliminates the branched aliphatic side chain entirely, creating a substantial cavity in the bilayer-embedded core. The local packing — sized for valine + the surrounding P504 backbone constraint — cannot fill the void without local rearrangement. The TM6-TM11 register through the C505/P885 cross-helix contact (discussed in C505Y, P885L Atlas cards) is perturbed.
The |ΔΔG| of 1.88 — close to the Cat 2 moderate-destabilization threshold — reflects substantial structural cost. AlphaMissense's 0.38 is below the 0.564 pathogenic threshold (AM under-call), but the documented DFNA6 hearing loss plus the substantial ΔΔG confirm pathogenicity.
Druggability Assessment
Mechanism: hydrophobic cavity creation in TM6 plus perturbation of the TM6-TM11 cross-helix register. Therapeutic strategy: same TM6 mid-helix microregion as P504L, C505Y, Y508C — pharmacological chaperone screening warranted given near-Cat-2 stability cost.
Why this matters
Feed this card to Wolfram Intelligence
Download the V503G 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.