F350I
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialPhenylalanine → Isoleucine at position 350 inside TM2. ClinVar Likely pathogenic. AlphaMissense 0.934, DynaMut2 ΔΔG +0.52 kcal/mol — STABILISING. Aromatic-to-branched-aliphatic substitution in a TM helix.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P346 | P346 | Preserved |
| Hydrogen bond | L347 | L347 | Preserved |
| Hydrogen bond | S353 | S353 | Preserved |
| Hydrogen bond | F354 | F354 | Preserved |
| Hydrogen bond | — | S418 | Gained |
| Polar contact | P346 | P346 | Preserved |
| Polar contact | L347 | L347 | Preserved |
| Polar contact | V348 | V348 | Preserved |
| Polar contact | L352 | L352 | Preserved |
| Polar contact | S353 | S353 | Preserved |
| Polar contact | F354 | F354 | Preserved |
| Polar contact | S418 | S418 | Preserved |
| Aromatic / π | F419 | — | Lost |
| Van der Waals | V348 | V348 | Preserved |
| Van der Waals | F354 | F354 | Preserved |
| Van der Waals | S418 | — | Lost |
| Hydrophobic | V415 | — | Lost |
| Hydrophobic | F419 | — | Lost |
| Hydrophobic | — | A422 | Gained |
| Hydrophobic | I427 | I427 | Preserved |
| Hydrophobic | L432 | — | 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 Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ single submitter. 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. |
|---|---|---|---|---|
| African / African American · under-sampled | 0.0030% | 1 / 33,480 | 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 350 sits in TM2. The AlphaFold model places F350 within 5 Å of ILE349 (2.5 Å), TYR351 (2.5 Å), SER418 (3.3 Å — TM2-TM3 cross-helix contact), SER353 (3.5 Å), and LEU347 (3.7 Å). The F350-S418 contact across helices is the structurally significant observation.
The wild-type phenylalanine's aromatic ring likely makes π-stacking or edge-face contact with Y351 and aromatic packing with the surrounding helices. Replacing it with isoleucine eliminates the aromatic character and replaces it with branched aliphatic packing. The DynaMut2 ΔΔG of +0.52 (stabilising) reflects that isoleucine packs efficiently into the local hydrophobic environment.
But AlphaMissense's 0.934 confirms severe functional consequence. The mechanism is loss of aromatic π-stacking with Y351 plus perturbation of the F350-S418 TM2-TM3 cross-helix contact.
Druggability Assessment
Mechanism is loss of aromatic packing with Y351 plus TM2-TM3 interface disruption at S418. Therapeutic strategy: site-directed at the F350-Y351-S418 contact cluster.
Why this matters
Feed this card to Wolfram Intelligence
Download the F350I 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.