F264L
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialPhenylalanine → Leucine at position 264 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.29 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.19 kcal/mol (stabilising). pLDDT 47 — Category 5 IDR territory.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | S261 | S261 | Preserved |
| Polar contact | S261 | — | Lost |
| Polar contact | S262 | S262 | Preserved |
| Polar contact | — | Q266 | Gained |
| Hydrophobic | I259 | — | 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
- pLDDT 47.03 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
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); 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 disorder
- 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
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; 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 African / African American: AF 0.021% (16 of 75,036 alleles), 20.2x 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. |
|---|---|---|---|---|
| African / African American | 0.021% | 16 / 75,036 | 0 | ~1 in 2340 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,496 | 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 264 sits in wolframin's N-terminal cytoplasmic domain at the boundary of the IDR. pLDDT of 47 is BELOW the 50 threshold — the Atlas formally classifies this position as Category 5 (IDR exclusion). DynaMut2 predictions in this region are not fully trustworthy.
Neighbors: LEU263 (2.5 Å), LEU265 (2.5 Å), SER261 (4.1 Å). The neighbor sparsity is itself an IDR signature.
AlphaMissense's 0.29 is below threshold. The Conflicting ClinVar classifications and the IDR localization together flag this variant as one where computational drug discovery should pause for wet-lab characterization.
Druggability Assessment
The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery.
Why this matters
Feed this card to Wolfram Intelligence
Download the F264L 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.