🧬 gnomAD Database

gnomAD Database

Use gnomAD when human genetic variant interpretation needs real population frequency and constraint context.

When To Use

• Check whether a variant is rare, common, or absent in the general population
• Compare ancestry-specific allele frequencies
• Use gene constraint metrics like pLI and LOEUF
• Support ACMG or ClinVar-style variant interpretation
• Prioritize candidate genes in rare disease analysis

Primary Resources

• Browser: https://gnomad.broadinstitute.org/
• GraphQL API: https://gnomad.broadinstitute.org/api
• Downloads: https://gnomad.broadinstitute.org/downloads

Practical Workflow

1. Identify the variant or gene and confirm the reference build.
2. Prefer gnomad_r4 for current GRCh38 work.
3. Check overall and ancestry-specific allele frequency.
4. Review consequence and loss-of-function annotations.
5. For gene-level work, examine LOEUF and related constraint metrics.
6. Combine gnomAD evidence with disease context rather than treating absence as proof of pathogenicity.

Interpretation Notes

• Rare does not mean pathogenic, but common usually argues against severe Mendelian causality
• LOEUF is generally more useful than pLI for current constraint work
• Homozygous counts matter for recessive interpretation
• Exome and genome datasets have different coverage tradeoffs

Best Practices

• Be explicit about GRCh37 vs GRCh38
• Check population breakdowns before making rarity claims
• Handle null or missing responses cleanly
• Batch and rate-limit API calls when querying many variants