Glossary

Plain-language definitions of the clinical-genetics terms used across the portal.

Constraint Classification Mechanism Population genetics ACMG criteria Inheritance

Constraint

pLI: pLI (probability of loss-of-function intolerance) is gnomAD’s probability that a gene is intolerant to heterozygous loss-of-function variants.; pLI ≥ 0.9 flags a gene where a single inactivating variant may be disease-causing (haploinsufficiency).
LOEUF: LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for the LoF observed/expected ratio — the preferred gnomAD v4 constraint metric. Lower = more intolerant to loss of function.; LOEUF < 0.35 marks a highly LoF-constrained gene.
Missense Z-score: How many standard deviations fewer missense variants are observed than expected across populations. Higher = more missense-constrained.; Z > 3.09 (p < 0.001) means the gene does not tolerate missense variation; OE missense < 0.6 is also considered constrained.
OE (LoF): The observed/expected ratio of loss-of-function variants in the population — how many LoF variants are seen versus expected by chance.; The upper CI bound (LOEUF) ≤ 0.35 indicates strong LoF constraint.
OE (missense): The observed/expected ratio of missense variants in the population.; OE ≤ 0.6 means fewer missense variants than expected — a missense-constraint signal.
pRec: pRec is gnomAD’s probability that a gene is intolerant to biallelic (recessive) loss of function while tolerating heterozygous loss of function.; pRec > 0.9 suggests heterozygous carriers are unaffected but biallelic loss is likely pathogenic.
Synonymous Z-score: A control metric — synonymous variants are largely neutral and expected near observed/expected = 1.0.; Large deviation usually points to annotation or coverage artifacts rather than biology.

Classification

VUS: Variant of Uncertain Significance — the evidence is insufficient to classify the variant as pathogenic or benign.; A VUS should not drive clinical decisions; reassess as new evidence emerges.
Pathogenic: A variant with strong evidence that it causes disease, per ACMG/AMP criteria.
Likely pathogenic: A variant with greater than ~90% certainty of being disease-causing, but short of the evidence required for Pathogenic.; Generally actionable like Pathogenic in most clinical contexts.
Benign / Likely benign: Benign means strong evidence the variant does not cause disease; Likely benign means greater than ~90% certainty it is harmless.
Conflicting interpretations: Different submitters have classified the variant differently (e.g. one Pathogenic, another VUS) — ClinVar’s “conflicting interpretations of pathogenicity”.; Inspect the individual submissions and their review status; weight expert-panel and recent assertions.
Review status (stars): ClinVar’s 0–4 gold-star review status reflects how much independent support a classification has — from no assertion criteria up to expert-panel/practice-guideline review.; ≥ 2 stars (multiple concordant submitters or an expert panel) is a stronger basis for clinical use.

Mechanism

Loss of function (LoF): The variant reduces or abolishes the gene product’s normal activity — e.g. via a premature stop, frameshift, or deletion.
Gain of function (GoF): The variant confers a new, increased, or constitutive activity rather than removing function.; Mechanism is variant-specific and needs functional/expert evidence; it is not inferable from gene-level data alone.
Dominant negative: The variant product interferes with the normal allele’s product (e.g. in multimeric proteins), causing more harm than simply losing one allele.
Haploinsufficiency: A single functional copy of the gene is not enough for normal function, so loss of one allele causes disease.; Suggested by high pLI / low LOEUF and ClinGen dosage haploinsufficiency scores.
Triplosensitivity: Having an extra copy (duplication) of the gene or region is itself harmful.; Assessed by ClinGen dosage triplosensitivity scores.

Population genetics

Allele frequency (AF): The fraction of chromosomes in a reference population (e.g. gnomAD) that carry the variant.; High population AF argues against a highly penetrant disease cause (ACMG BA1/BS1).
Popmax: The highest allele frequency across the individual gnomAD ancestry groups, rather than the global average.; Used instead of global AF so a variant common in one ancestry is not missed.
faf95: The filtering allele frequency — the 95% confidence lower bound of the popmax AF. A conservative “is this too common to be pathogenic?” threshold.; faf95 above a disease’s maximum credible AF supports a benign classification (BS1/BA1).

ACMG criteria

PVS1: ACMG “pathogenic very strong”: a null variant (nonsense, frameshift, canonical splice, etc.) in a gene where loss of function is a known disease mechanism.
PM2: ACMG “pathogenic moderate” (commonly applied as Supporting): the variant is absent or extremely rare in population databases.
PP3 / BP4: ACMG computational evidence: in-silico predictors agree the variant is damaging (PP3, supports pathogenic) or benign (BP4, supports benign).
BA1 / BS1: ACMG population evidence for benign: the allele frequency is too high for a disease cause — stand-alone (BA1) or strong (BS1).

Inheritance

De novo: A variant present in the patient but in neither parent (newly arisen). Confirmed de novo status is ACMG evidence for pathogenicity (PS2/PM6).
Penetrance: The proportion of people carrying a pathogenic genotype who actually show the phenotype. Reduced penetrance means some carriers are unaffected.