Y650D
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialTyrosine → Aspartate at position 650 inside TM10. ClinVar Likely pathogenic. AlphaMissense 0.829, DynaMut2 ΔΔG +0.38 STABILISING. pLDDT 69 borderline. Same position as Y650H (Atlas card adjacent) but with charge introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I338 | — | Lost |
| Hydrogen bond | F646 | F646 | Preserved |
| Hydrogen bond | C647 | C647 | Preserved |
| Hydrogen bond | R653 | — | Lost |
| Hydrogen bond | S654 | S654 | Preserved |
| Polar contact | F646 | F646 | Preserved |
| Polar contact | C647 | C647 | Preserved |
| Polar contact | W648 | W648 | Preserved |
| Polar contact | Y652 | — | Lost |
| Polar contact | R653 | R653 | Preserved |
| Polar contact | S654 | S654 | Preserved |
| Van der Waals | W648 | W648 | 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
- transmembrane position; predictor benchmarked on soluble proteins
- pLDDT 68.69 below 70
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.
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
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 Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in South Asian: AF 0.016% (15 of 91,090 alleles), 15.6x 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 | 0.016% | 15 / 91,090 | 0 | ~1 in 3040 |
| Remaining individuals | 0.0032% | 2 / 62,482 | 0 | ~1 in 15620 |
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 650 sits at the end of TM10, in the same aromatic-rich pocket discussed in the Y650H Atlas card: PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å), PHE646 (3.7 Å), TRP648 (4.4 Å).
Replacing tyrosine with aspartate is more disruptive than Y650H. Y650H preserved aromatic character (histidine imidazole). Y650D eliminates the aromatic ring entirely and introduces a small carboxylate where the wild-type phenol provided bulky aromatic packing. The aromatic cluster (F646, F649, W648) loses its tyrosine partner; the new carboxylate is also unfavorable in the bilayer-embedded environment.
The DynaMut2 ΔΔG of +0.38 (stabilising) is surprising — possibly because the aspartate can extend toward the lumenal face of TM10 where its charge is more compatible. AlphaMissense's 0.829 + ClinVar Pathogenic confirm severe functional consequence despite the stabilization.
Druggability Assessment
Mechanism is loss of Y650 aromatic packing with the TM10 C-terminal aromatic cluster (F646, F649, W648). Therapeutic strategy: same microregion as Y650H.
Why this matters
Feed this card to Wolfram Intelligence
Download the Y650D 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.