A874T
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialAlanine → Threonine at position 874 inside TM11. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.33 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.49 kcal/mol (destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | F417 | Gained |
| Hydrogen bond | T870 | T870 | Preserved |
| Hydrogen bond | V871 | V871 | Preserved |
| Hydrogen bond | F877 | F877 | Preserved |
| Hydrogen bond | A878 | A878 | Preserved |
| Polar contact | — | F417 | Gained |
| Polar contact | — | P420 | Gained |
| Polar contact | T870 | T870 | Preserved |
| Polar contact | V871 | V871 | Preserved |
| Polar contact | H872 | — | Lost |
| Polar contact | F877 | F877 | Preserved |
| Polar contact | A878 | A878 | Preserved |
| Van der Waals | — | P420 | Gained |
| Van der Waals | V871 | V871 | Preserved |
| Van der Waals | H872 | — | Lost |
| Van der Waals | — | K876 | Gained |
| Hydrophobic | — | F417 | Gained |
| Hydrophobic | P420 | — | Lost |
| Hydrophobic | I421 | I421 | Preserved |
| Hydrophobic | — | V871 | Gained |
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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); 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 syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; 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.
Highest in Middle Eastern: AF 0.165% (10 of 6,062 alleles), 16.3x 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. |
|---|---|---|---|---|
| Middle Eastern | 0.165% | 10 / 6,062 | 0 | ~1 in 300 |
| East Asian | 0.029% | 13 / 44,888 | 0 | ~1 in 1730 |
| European (non-Finnish) | 0.011% | 128 / 1,180,044 | 0 | ~1 in 4610 |
| Remaining individuals | 0.0080% | 5 / 62,502 | 0 | ~1 in 6250 |
| African / African American | 0.0067% | 5 / 75,080 | 0 | ~1 in 7510 |
| Admixed American | 0.0033% | 2 / 60,034 | 0 | ~1 in 15010 |
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 874 sits in TM11 near its start. Neighbors: GLY873 (2.5 Å), VAL875 (2.5 Å — partner of V875M), VAL871 (3.6 Å — partner of V871G and V871M!). The local environment is densely populated by Atlas variant positions: V871G/V871M, V875M, K876T, and now A874T.
Replacing A874 with threonine introduces polarity into the bilayer-embedded TM11 environment. The hydroxyl is energetically unfavorable in the lipid context and pulls the local geometry toward the membrane-water interface.
|ΔΔG| 0.49 + AM 0.33 under-call + Wolfram + Wolfram-like confirm pathogenicity.
Druggability Assessment
Mechanism: polarity introduction into TM11 bilayer-embedded position. Therapeutic strategy: TM11 multi-variant cluster (V871G/M, V875M, K876T, A874T).
Why this matters
Feed this card to Wolfram Intelligence
Download the A874T 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.