Variants586
MECP2548
Absent493
Absent + ultra-rare99.8%
How often are Rett-associated pathogenic or likely pathogenic alleles observed in gnomAD?
The revised session assembled 586 unique ClinVar variants across eight Rett-associated genes or loci, then matched queryable alleles to gnomAD by genomic coordinates and alleles.
- ClinVar criteria
- Pathogenic or likely pathogenic; Rett syndrome
- Gene distribution
- 548 MECP2, 19 CDKL5, 10 FOXG1, 9 other
- Frequency bins
- Absent, ultra-rare, rare, and more common
- Revised method
- Allele-specific gnomAD matching
ClinVar retrieval, normalization, allele matching, and review
Collect variantsQueried and deduplicated Rett-associated pathogenic and likely pathogenic ClinVar records.
Prepare allelesExtracted queryable coordinates and reference/alternate alleles across relevant genes.
Match gnomADUsed allele-specific records rather than gene-level frequency summaries.
Review edge casesFlagged API failures, structural variants, and normalization-dependent indels for follow-up.
Nearly all analyzed variants were absent or ultra-rare, but not all
493 absent
84.1% of the 586 variants were classified as absent from the matched gnomAD records.
92 ultra-rare
15.7% had allele frequency below 1 × 10⁻⁴; 81 were below 1 × 10⁻⁵.
One rare variant
MECP2 c.1183_1210del had AF 1.45 × 10⁻⁴, placing it in the rare—not ultra-rare—bin.
Corrected aggregate
585 of 586 variants, or 99.8%, were absent or ultra-rare.
Unresolved records can bias the absent category
- Nine variants from minor loci could not be retrieved through the gnomAD API and were classified absent by default; they require manual verification.
- Five copy-number variants are not matchable to the short-variant dataset and should be checked in gnomAD-SV.
- Fallback indel normalization may miss equivalent left-normalized representations.
- Chromosome X frequencies use combined population values and may obscure sex-specific context.
- ClinVar classifications and gnomAD snapshots change over time.
Confidence boundary
Strongest for successfully allele-matched records. The default-absent API failures and unmatchable structural variants must not be interpreted as confirmed population absence.
Reproducibility artifacts recorded in the session
rett_clinvar_variants.csvClinVar source setrett_queryable_variants.csvCoordinate-ready allelesrett_variants_gnomad_allele_matched.csvRevised match resultsgnomad_rett_genes.jsongnomAD response datafig1–fig4Revised summary figuresOriginal session report10-page PDF with revised allele-specific results, figures, caveats, and recorded runtime of 130.1 seconds.
Download PDF