Glossary

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

Constraint Classification Mechanism Population genetics ACMG criteria Inheritance Protein classes

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.

Protein classes

Voltage-gated channel: A membrane pore that opens and closes in response to the electrical voltage across the cell membrane, letting specific ions (sodium, potassium, calcium) flow through. Neurons depend on these to fire and reset.; Variants can make the channel underactive or overactive — and the treatment implications often flip depending on which (see the gene’s mechanism panel).
Ligand- / stimulus-gated channel: A membrane pore that opens in response to a stimulus other than voltage — a chemical messenger binding it (glutamate, GABA — the receiving end of a synapse), or a physical stimulus like stretch or touch (PIEZO, TRP channels).
Transporter / pump: A membrane protein that carries specific molecules across the membrane — glucose, neurotransmitters, ions — either passively or by burning energy (a pump).
G-protein coupled receptor: A membrane receptor that snakes through the membrane seven times and relays signals from outside the cell to G-proteins inside — the largest receptor family in the genome.
Kinase: An enzyme that switches other proteins on or off by attaching phosphate groups to them — a central currency of cellular signaling.
Chaperone / protein folding: A protein that helps other proteins fold correctly, or refold when stressed — quality control for the cell’s protein factory. Chaperone defects often cause disease through the slow accumulation of misfolded protein.
Secreted protein / growth factor: A protein exported out of the cell to act elsewhere — growth factors, neuropeptides, trophic signals. Disease usually reflects too little of the signal reaching its target cells.
Enzyme: A protein that performs a chemical reaction — building, breaking, or converting molecules. Enzyme deficiencies often cause recessive metabolic disease, and some are treatable by supplying the missing product or restricting the substrate.
Chromatin / epigenetic regulator: A protein that reads, writes, or reshapes the packaging of DNA (chromatin), controlling which genes are available to be switched on — without changing the DNA sequence itself.
Transcription factor: A protein that binds specific DNA sequences and switches target genes on or off. Many neurodevelopmental disorders are caused by losing one working copy of a transcription factor.
RNA binding / translation / splicing: A protein that handles RNA — splicing it, transporting it, or translating it into protein. Errors here affect many downstream genes at once.
Signaling regulator: A protein that switches cellular signaling pathways on or off — GTPases and their regulators, the mTOR growth axis, second-messenger enzymes. Many act as brakes; losing a brake overactivates the pathway.
Vesicle / trafficking protein: A protein that moves cargo around the cell in membrane bubbles (vesicles) — including the machinery that releases neurotransmitter at synapses.
Synaptic scaffold / adaptor: A protein with no enzymatic activity of its own that holds other proteins in the right place and combination — the organizing framework of structures like the postsynaptic density.
Cell adhesion / ECM protein: A protein that connects cells to each other or to the surrounding matrix — how neurons recognize partners, form circuits, and how muscle anchors to its scaffolding.
Cytoskeletal / structural protein: A building-block protein of the cell’s internal skeleton — tubulins, actins, spectrins, filaments — providing shape, transport rails, and mechanical strength.