L549M
AlphaMissense: likely benign (0.11)Uncertain significanceTransmembrane · predictedInteractive 3D Structure
Computational Predictions
AlphaMissense + AlphaFold card. This variant is mapped from AlphaMissense pathogenicity and AlphaFold confidence. The DynaMut2 ΔΔG stability prediction and the wild-type/mutant structural comparison (dual-pane + bond network) are computed per-variant and backfill here — they require a DynaMut2 submission, unlike the precomputed AlphaMissense score.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Uncertain significance for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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: 2★ multiple submitters, no conflicts. 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.
Full Variant Card
L549M — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Leucine (L) → Methionine (M) at position 549 Domain context: Transmembrane helix 8
AlphaMissense
- Pathogenicity score: 0.1061
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 549: 82.94
DynaMut2 ΔΔG: not yet computed for this variant — AlphaMissense + AlphaFold confidence shown above. Stability ΔΔG and the wild-type/mutant structural comparison backfill behind this note.
Clinical evidence
Inheritance and scope
Uncertain significance — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296)
ClinVar classifies this variant as Uncertain significance for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
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.
- Classification: Uncertain significance
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: Wolfram syndrome 1; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome
- cDNA change: c.1645C>A
- ClinVar accession: VCV001378166
- Last evaluated: 2024/02/21 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.612623Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the L549M 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.