T527I
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialThreonine → Isoleucine at position 527 in connecting loop. ClinVar Conflicting including WFS1-related + DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.53.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F524 | F524 | Preserved |
| Hydrogen bond | L531 | L531 | Preserved |
| Hydrogen bond | V532 | V532 | Preserved |
| Polar contact | F524 | F524 | Preserved |
| Polar contact | K525 | K525 | Preserved |
| Polar contact | L531 | L531 | Preserved |
| Polar contact | V532 | V532 | Preserved |
| Van der Waals | — | F524 | Gained |
| Van der Waals | K525 | — | Lost |
| Van der Waals | L531 | L531 | Preserved |
| Hydrophobic | A519 | A519 | Preserved |
| Hydrophobic | — | L531 | 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 at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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 spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder; WFS1-Related Spectrum Disorders
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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 Finnish: AF 0.011% (7 of 62,378 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| Finnish | 0.011% | 7 / 62,378 | 0 | ~1 in 4460 |
| European (non-Finnish) | 0.0075% | 88 / 1,180,040 | 0 | ~1 in 6700 |
| Remaining individuals | 0.0048% | 3 / 62,476 | 0 | ~1 in 10410 |
| African / African American | 0.0040% | 3 / 74,944 | 0 | ~1 in 12490 |
| East Asian · under-sampled | 0.0022% | 1 / 44,898 | 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 527 in connecting loop near TM7 start (TM7 = 529-549). Neighbors: TYR528 (2.5 Å), GLY526 (2.5 Å), LEU531 (3.9 Å — same L531 in L543P TM7 region).
T527I T→I substitution at the loop-TM7 boundary. AM 0.12 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: T→I lost H-bonding at TM7 boundary. Therapeutic: loop-TM7 boundary microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the T527I 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.