V415F
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialValine → Phenylalanine at position 415 inside TM3. ClinVar Likely pathogenic, Cataract 41. AlphaMissense 0.574 (just above threshold), DynaMut2 ΔΔG -1.64 kcal/mol (destabilising) — close to Cat 2. Volume increase in TM3.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M357 | — | Lost |
| Hydrogen bond | S411 | S411 | Preserved |
| Hydrogen bond | V412 | V412 | Preserved |
| Hydrogen bond | S418 | S418 | Preserved |
| Hydrogen bond | F419 | F419 | Preserved |
| Polar contact | S353 | — | Lost |
| Polar contact | S411 | S411 | Preserved |
| Polar contact | V412 | V412 | Preserved |
| Polar contact | F413 | F413 | Preserved |
| Polar contact | F417 | — | Lost |
| Polar contact | S418 | S418 | Preserved |
| Polar contact | F419 | F419 | Preserved |
| Aromatic / π | — | F350 | Gained |
| Aromatic / π | — | F354 | Gained |
| Van der Waals | S353 | — | Lost |
| Van der Waals | — | F354 | Gained |
| Van der Waals | — | V412 | Gained |
| Van der Waals | — | F413 | Gained |
| Van der Waals | F417 | — | Lost |
| Van der Waals | F419 | F419 | Preserved |
| Hydrophobic | F350 | F350 | Preserved |
| Hydrophobic | F354 | F354 | Preserved |
| Hydrophobic | M357 | M357 | Preserved |
| Hydrophobic | L543 | L543 | Preserved |
| Hydrophobic | — | I547 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic for Cataract 41 (autosomal dominant, OMIM 116400). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- No assertion criteria were provided (0★). Treat the conditions above as unverified submissions, 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: 0★ no assertion criteria provided. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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 415 sits in TM3. The AlphaFold model places V415 within 5 Å of ILE416 (2.5 Å), PHE414 (2.5 Å — already aromatic), SER418 (3.6 Å), VAL412 (3.6 Å), and SER353 (3.8 Å — TM2-TM3 cross-helix, same S353 as F350I Atlas card neighbor).
Replacing V415 with phenylalanine creates a tandem aromatic motif (F414-F415). The local TM3 packing is reorganized to accommodate the second aromatic ring. The TM2-TM3 cross-helix S353 contact (also touched by F350I) is perturbed.
The |ΔΔG| of 1.64 — close to the Cat 2 threshold — reflects substantial fold cost. AlphaMissense's 0.574 is borderline-pathogenic plus Cataract 41 clinical evidence confirms pathogenic consequence.
Druggability Assessment
Mechanism is volume mismatch in TM3 plus disruption of TM2-TM3 cross-helix contact (S353). Therapeutic strategy: TM2-TM3 interface site-directed design — same target as F350I.
Why this matters
Feed this card to Wolfram Intelligence
Download the V415F 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.