Idiopathic generalized epilepsy: genes and variants

Genes linked to Idiopathic generalized epilepsy

• GABRA1: Gamma-aminobutyric acid receptor subunit alpha-1

  The gene product supplies the alpha-1 subunit of a pentameric GABA-A receptor, a ligand-gated chloride channel in the brain. GABA binding allows chloride influx that dampens neuronal activity, making this receptor important for inhibition and seizure biology.

  20 disease-causing and 159 uncertain variants in GABRA1 are linked to Idiopathic generalized epilepsy.

• CASR: Extracellular calcium-sensing receptor

  It senses extracellular calcium in the parathyroid gland and kidney and adjusts parathyroid-hormone secretion and renal calcium handling accordingly. Loss-of-function variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, whereas activating variants cause autosomal dominant hypocalcemia.

  0 disease-causing and 1 uncertain variants in CASR are linked to Idiopathic generalized epilepsy.

• KCNMA1: Calcium-activated potassium channel subunit alpha-1

  Its large-conductance potassium current couples membrane voltage and intracellular calcium to rapid repolarization in neurons, smooth muscle, and other excitable cells. Gain- and loss-of-function variants can cause paroxysmal dyskinesia, epilepsy, developmental impairment, and movement disorders.

  0 disease-causing and 0 uncertain variants in KCNMA1 are linked to Idiopathic generalized epilepsy.

• SLC2A1: Solute carrier family 2, facilitated glucose transporter member 1

  It provides basal glucose uptake in many tissues and is the principal route for glucose entry across the blood-brain barrier. Haploinsufficiency causes GLUT1 deficiency syndrome with epilepsy, developmental impairment, and movement disorders from inadequate brain glucose delivery.

  0 disease-causing and 0 uncertain variants in SLC2A1 are linked to Idiopathic generalized epilepsy.

• ABCB1: ATP-dependent translocase ABCB1

  It uses ATP to export a broad range of drugs and xenobiotics across intestinal, hepatic, renal, blood-brain-barrier, and other membranes. Its activity strongly influences drug absorption and tissue exposure and can contribute to multidrug resistance in cancer.

  1 disease-causing and 0 uncertain variants in ABCB1 are linked to Idiopathic generalized epilepsy.

Where Idiopathic generalized epilepsy variants cluster

• GABRA1 Transmembrane (positions 280–301): 5 of 20 disease-causing changes, 5.2× more than its size predicts.

Known disease-causing variants in Idiopathic generalized epilepsy

Uncertain variants in Idiopathic generalized epilepsy that look disease-causing

Which prediction tools work for Idiopathic generalized epilepsy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 79 out of 100
• SIFT: 72 out of 100

Diseases related to Idiopathic generalized epilepsy

• Epilepsy, idiopathic generalized, susceptibility to, 13, also linked to CASR, GABRA1, KCNMA1 and SLC2A1
• Hypertrophic cardiomyopathy, also linked to CASR
• Familial hypocalciuric hypercalcemia, also linked to CASR
• EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2, also linked to GABRA1
• Autosomal dominant hypocalcemia, also linked to CASR
• GLUT1 deficiency syndrome, also linked to SLC2A1
• Encephalopathy due to GLUT1 deficiency, also linked to SLC2A1
• Childhood onset GLUT1 deficiency syndrome 2, also linked to SLC2A1
• Epilepsy, also linked to GABRA1
• Nephrolithiasis/nephrocalcinosis, also linked to CASR
• Neonatal severe primary hyperparathyroidism, also linked to CASR
• Generalized epilepsy-paroxysmal dyskinesia syndrome, also linked to KCNMA1

Frequently asked questions

Which genes are linked to Idiopathic generalized epilepsy?

In CATVariant, Idiopathic generalized epilepsy is linked to 5 analyzed proteins: GABRA1 (Gamma-aminobutyric acid receptor subunit alpha-1), CASR (Extracellular calcium-sensing receptor), KCNMA1 (Calcium-activated potassium channel subunit alpha-1), SLC2A1 (Solute carrier family 2, facilitated glucose transporter member 1) and ABCB1 (ATP-dependent translocase ABCB1).

How many genetic variants are linked to Idiopathic generalized epilepsy?

194 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 160 are of uncertain significance or have conflicting reports.

Which uncertain variants in Idiopathic generalized epilepsy look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GABRA1 R214S, GABRA1 N275S and GABRA1 E277D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Idiopathic generalized epilepsy?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.79, based on 16 disease-causing and 9 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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