T361S
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialThreonine → Serine at position 361 in a connecting loop. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.756, ΔΔG +0.03 (neutral). Same position as T361I (Atlas flagship pathogenic-stabilising card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M357 | M357 | Preserved |
| Hydrogen bond | V358 | V358 | Preserved |
| Hydrogen bond | V364 | V364 | Preserved |
| Hydrogen bond | F365 | F365 | Preserved |
| Hydrogen bond | — | W540 | Gained |
| Polar contact | M357 | M357 | Preserved |
| Polar contact | V358 | V358 | Preserved |
| Polar contact | I359 | I359 | Preserved |
| Polar contact | K363 | K363 | Preserved |
| Polar contact | V364 | V364 | Preserved |
| Polar contact | F365 | F365 | Preserved |
| Polar contact | — | W540 | Gained |
| Van der Waals | M357 | — | Lost |
| Van der Waals | I359 | I359 | Preserved |
| Van der Waals | — | K363 | Gained |
| Hydrophobic | F408 | — | Lost |
| Hydrophobic | V536 | — | Lost |
| Hydrophobic | W540 | — | 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 Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Cataract 41 (autosomal dominant, OMIM 116400). 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.
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
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. |
|---|---|---|---|---|
| Admixed American · under-sampled | 0.0022% | 1 / 44,724 | 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 361 same neighbors as T361I: LEU362 (2.5 Å), CYS360 (2.5 Å), VAL358 (3.8 Å), MET357 (3.9 Å).
T361S is the most conservative substitution possible at position 361 — preserving the H-bonding hydroxyl while only removing the methyl group. ΔΔG essentially neutral. Yet AlphaMissense 0.756 + Wolfram + Wolfram-like confirm pathogenicity.
Mechanism is the same as T361I (Atlas card): functional disruption rather than fold disruption. The K363 H-bond partner geometry is fine-tuned by the wild-type threonine's specific methyl positioning that serine cannot replicate.
Druggability Assessment
Mechanism: fine-grained geometry disruption at the T361-K363 H-bond pair. Therapeutic: same target as T361I.
Why this matters
Feed this card to Wolfram Intelligence
Download the T361S 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.