Documentation / Reference Databases / gnomAD
gnomAD allele frequency in variant classification
gnomAD provides population allele frequencies and gene-constraint measurements from large exome and genome cohorts. Folklore uses managed GRCh38 gnomAD v4.1 data to evaluate whether population evidence may support BA1, BS1, BS2, or PM2 and whether gene constraint is compatible with selected loss-of-function or missense evidence paths. Frequency and constraint do not classify a variant on their own.
The files are stored locally. No case variant or patient information is sent to gnomAD during processing.
Review one public GRCh38 variant against Folklore's current evidence snapshot. Public search accepts a variant expression only. Do not enter patient or case information.
Search a public variantAllele Frequency Evidence
The managed dataset includes global frequency, ancestry-group maximum frequency, allele count, allele number, homozygote count, and source quality state. The classifier evaluates the field defined for the criterion path and records which frequency context was used. A high frequency can weigh against a rare highly penetrant disorder, but the appropriate threshold depends on disease prevalence, penetrance, inheritance, founder effects, and gene-specific guidance.
ACMG Criteria Using Variant Frequencies
The default threshold is at least 5% using the eligible ancestry-group maximum frequency path. Source quality, missing-data, and gene-specific threshold guards still apply.
Frequency exceeds the maximum credible value for the disorder. The current defaults distinguish eligible autosomal dominant and autosomal recessive contexts, while VCEP or curated gene-specific thresholds can replace a default.
An eligible homozygote-count path can support tolerance of the genotype. Inheritance, penetrance, age of onset, source quality, and the applicable disease mechanism remain material.
Absence or extreme rarity can contribute PM2. The operative field and strength can follow a gene-specific specification; an unavailable or bottlenecked frequency state is not silently treated as absence.
Frequency Columns (6)
Global allele frequency across all included groups. Retained for provenance and used by criterion paths whose configured threshold is defined against global frequency.
Global allele count. Number of times the alternate allele was observed across all samples.
Global allele number. Total number of alleles genotyped at this position. Used to assess coverage adequacy.
Global homozygote count. Number of individuals homozygous for the alternate allele. Used for BS2 (>15 homozygotes).
Maximum allele frequency across eligible ancestry groups. The current default BA1 and BS1 paths use this field when it is present and positive.
Population with the highest allele frequency. Reports which ancestry group shows the highest frequency for this variant.
Ancestry Groups
gnomAD v4.1 categorizes individuals into 8 genetic ancestry groups. The popmax field reports which group shows the highest allele frequency for a given variant, which can be clinically relevant for population-specific disease prevalence.
| Code | Ancestry Group | Approximate Samples |
|---|---|---|
| AFR | African / African American | ~30,000 |
| AMR | Admixed American / Latino | ~16,000 |
| ASJ | Ashkenazi Jewish | ~5,000 |
| EAS | East Asian | ~10,000 |
| FIN | Finnish | ~13,000 |
| MID | Middle Eastern | ~3,000 |
| NFE | Non-Finnish European | ~450,000 |
| SAS | South Asian | ~19,000 |
Note: Non-Finnish European (NFE) represents the majority of the cohort. Variants enriched in underrepresented populations may have less precise frequency estimates.
gnomAD Gene Constraint
A separate gnomAD dataset provides gene-level constraint metrics. Variant frequencies describe observations for a specific allele. Constraint compares observed and expected variation across a gene. Folklore uses these measurements as eligibility signals inside guarded criterion paths. Constraint is not evidence that every rare variant in a constrained gene is pathogenic.
ACMG Criteria Using Gene Constraint
The default constraint gate accepts pLI above 0.9 or LOEUF below 0.45. Consequence, transcript position, disease association, mechanism, inheritance, and other safeguards determine eligibility and final strength.
The current missense criterion path requires pLI above 0.5 and missense Z-score above 2.0, together with disease-association and missense-mechanism safeguards. Constraint alone does not establish PP2.
A low-constraint signal can contribute to BP1 only when the disease mechanism is primarily truncating and the missense-mechanism exclusion guards are satisfied.
Constraint Columns (4)
Probability of loss-of-function intolerance. The current default PVS1 constraint gate uses pLI above 0.9 as one eligible signal, subject to disease-mechanism and consequence safeguards.
Loss-of-function observed/expected upper bound fraction. Lower values indicate stronger constraint. The current default PVS1 constraint gate uses LOEUF below 0.45 as an alternative eligible signal.
Loss-of-function observed/expected ratio. The point estimate of how many LoF variants are observed versus expected. LOEUF is the upper confidence bound of this ratio.
Missense Z-score. Positive values indicate the gene has fewer missense variants than expected (missense-constrained). Used in the Screening Service for gene relevance scoring.
pLI vs. LOEUF
pLI is a probability from a discrete loss-of-function constraint model. LOEUF is the upper confidence bound of the observed-to-expected loss-of-function ratio and provides a continuous measure. The current default Folklore gate accepts pLI above 0.9 or LOEUF below 0.45 as one part of PVS1 eligibility. The other PVS1 safeguards still apply, and a gene-specific specification can change the applicable rule.
Limitations
Cohort composition and sample inclusion criteria affect frequency estimates. Review the applicable gnomAD dataset documentation together with the ancestry, coverage, disease, and inheritance context for the record.
Coverage varies across the genome. Low-coverage regions may have NULL frequency data, which prevents PM2 from triggering.
Structural variants and complex rearrangements are not represented in the SNV/indel dataset.
Population ancestry group assignment is based on principal component analysis, not self-reported ethnicity.
Rare variants in underrepresented populations may have inflated or absent frequency estimates due to smaller sample sizes.
Gene constraint metrics reflect population-level observations. A gene with low pLI may still harbor pathogenic variants in specific domains or functional regions.
Constraint metrics are gene-wide averages. They do not capture regional variation in constraint within a gene.
Population frequency is not a diagnosis and cannot establish benignity without the disease, inheritance, penetrance, and source-quality context required by the criterion.
References
Chen S, et al. "A genomic mutational constraint map using variation in 76,156 human genomes." Nature. 2024;625:92-100. PMID: 38057664
Karczewski KJ, et al. "The mutational constraint spectrum quantified from variation in 141,456 humans." Nature. 2020;581:434-443. PMID: 32461654
Continue with the ACMG/AMP framework or compare computational splice evidence in SpliceAI precomputed scores.