M306T
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialMethionine → Threonine at position 306 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.03 (neutral).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Y302 | Y302 | Preserved |
| Hydrogen bond | L303 | — | Lost |
| Hydrogen bond | A310 | A310 | Preserved |
| Polar contact | Y302 | Y302 | Preserved |
| Polar contact | L303 | L303 | Preserved |
| Polar contact | I304 | I304 | Preserved |
| Polar contact | A310 | A310 | Preserved |
| Van der Waals | Y302 | Y302 | Preserved |
| Van der Waals | I304 | I304 | Preserved |
| Hydrophobic | Y302 | — | 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
- pLDDT 65.69 below 70
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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); 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 diabetesautosomal dominantsubmitted as: Monogenic diabetes
- 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 African / African American: AF 1.33% (998 of 74,986 alleles), 19.5x the global figure. The global AF describes the general population, not the at-risk group.
9 homozygotes reported in gnomAD v4 (9 African / African American). 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. |
|---|---|---|---|---|
| African / African American | 1.33% | 998 / 74,986 | 9 | ~1 in 38 |
| Remaining individuals | 0.069% | 43 / 62,504 | 0 | ~1 in 730 |
| Admixed American | 0.053% | 32 / 60,014 | 0 | ~1 in 940 |
| South Asian | 0.0044% | 4 / 91,080 | 0 | ~1 in 11390 |
| European (non-Finnish) | 0.0021% | 25 / 1,179,980 | 0 | ~1 in 23600 |
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 306 near TM1 boundary. Neighbors: ASP305 (2.5 Å), ALA307 (2.5 Å — partner of S308C!), LEU303 (3.9 Å).
M306T near the S308C variant region. Loss of methionine-specific chemistry + introduced polarity. AM 0.14 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: lost methionine chemistry near TM1 boundary. Therapeutic: same 305-308 microregion as S308C.
Why this matters
Feed this card to Wolfram Intelligence
Download the M306T 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.