F329I
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialPhenylalanine → Isoleucine at position 329 inside TM1. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.22.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N325 | N325 | Preserved |
| Hydrogen bond | A326 | A326 | Preserved |
| Hydrogen bond | I332 | I332 | Preserved |
| Hydrogen bond | V333 | V333 | Preserved |
| Polar contact | N325 | N325 | Preserved |
| Polar contact | A326 | A326 | Preserved |
| Polar contact | F331 | — | Lost |
| Polar contact | I332 | I332 | Preserved |
| Polar contact | V333 | V333 | Preserved |
| Van der Waals | L327 | L327 | Preserved |
| Van der Waals | F331 | F331 | Preserved |
| Van der Waals | V333 | V333 | Preserved |
| Hydrophobic | V333 | V333 | 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
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 WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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 Spectrum Disorders
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 0.050% (3 of 6,060 alleles), 3.2x 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 | 0.050% | 3 / 6,060 | 0 | ~1 in 1010 |
| Admixed American | 0.032% | 19 / 60,018 | 0 | ~1 in 1580 |
| East Asian | 0.029% | 13 / 44,862 | 0 | ~1 in 1730 |
| South Asian | 0.026% | 24 / 91,066 | 0 | ~1 in 1900 |
| European (non-Finnish) | 0.015% | 173 / 1,179,956 | 0 | ~1 in 3410 |
| Remaining individuals | 0.011% | 7 / 62,502 | 0 | ~1 in 4460 |
| African / African American | 0.011% | 8 / 75,012 | 0 | ~1 in 4690 |
| Finnish | 0.0062% | 4 / 64,040 | 0 | ~1 in 8010 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,606 | 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 329 in TM1. Neighbors: ILE328 (2.5 Å), PHE330 (2.5 Å — F330-F331 cluster region; F331I!), ASN325 (3.6 Å — A325 in A326 region).
F329I loses aromatic. Adjacent to F331I (Atlas card). Both perturb the F329-F330-F331 aromatic cluster. AM 0.15 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: aromatic loss in F329-F330-F331 TM1 cluster. Therapeutic: TM1 multi-variant target.
Why this matters
Feed this card to Wolfram Intelligence
Download the F329I 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.