Generalized epilepsy with febrile seizures plus: genes and variants

Genes linked to Generalized epilepsy with febrile seizures plus

• SCN1A: Sodium channel protein type 1 subunit alpha

  Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine.

  76 disease-causing and 86 uncertain variants in SCN1A are linked to Generalized epilepsy with febrile seizures plus.

• SCN9A: Sodium channel protein type 9 subunit alpha

  The protein forms Nav1.7, a voltage-gated sodium channel that amplifies electrical signals in peripheral sensory neurons. Changes in Nav1.7 activity can produce either excessive pain or congenital insensitivity to pain, making SCN9A central to pain biology.

  14 disease-causing and 1,193 uncertain variants in SCN9A are linked to Generalized epilepsy with febrile seizures plus.

• HCN1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1

  The protein forms a hyperpolarization-activated channel that conducts both potassium and sodium ions. It contributes to pacemaker currents and the neuronal I(h) current that shapes excitability, and HCN1 variants are associated with developmental epilepsy syndromes.

  10 disease-causing and 17 uncertain variants in HCN1 are linked to Generalized epilepsy with febrile seizures plus.

• GABRG2: Gamma-aminobutyric acid receptor subunit gamma-2

  The gene product supplies the gamma-2 subunit of synaptic GABA-A receptors, which are pentameric chloride channels activated by the inhibitory neurotransmitter GABA. The subunit helps receptor assembly and localization at neuronal membranes, and GABRG2 variants are associated with several epilepsy syndromes.

  0 disease-causing and 0 uncertain variants in GABRG2 are linked to Generalized epilepsy with febrile seizures plus.

Weakly linked (only a few uncertain records): RELN.

Where Generalized epilepsy with febrile seizures plus variants cluster

• SCN1A S4 of repeat IV (positions 1637–1655): 4 of 76 disease-causing changes, 5.6× more than its size predicts.
• SCN9A Cytoplasmic (positions 1458–1514): 3 of 14 disease-causing changes, 7.5× more than its size predicts.
• SCN1A Pore-forming (positions 939–952): 3 of 76 disease-causing changes, 5.7× more than its size predicts.
• SCN9A II (positions 726–989): 5 of 14 disease-causing changes, 2.7× more than its size predicts.
• SCN1A I (positions 110–454): 20 of 76 disease-causing changes, 1.5× more than its size predicts.

Known disease-causing variants in Generalized epilepsy with febrile seizures plus

Showing 60 of 100.

Which prediction tools work for Generalized epilepsy with febrile seizures plus

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

• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 90 out of 100
• AlphaGenome (regulatory): 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 89 out of 100
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 82 out of 100
• MutPred2: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 80 out of 100
• AlphaGenome (splicing): 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 66 out of 100

Same protein, different disease

• Early-infantile DEE is also caused by SCN1A variants; they fall partly in the same places as the Generalized epilepsy with febrile seizures plus variants (422 disease-causing).
• Severe myoclonic epilepsy in infancy is also caused by SCN1A variants; they fall partly in the same places as the Generalized epilepsy with febrile seizures plus variants (213 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by SCN1A variants; they fall partly in the same places as the Generalized epilepsy with febrile seizures plus variants (20 disease-causing).
• Autosomal dominant epilepsy is also caused by SCN1A variants; they fall partly in the same places as the Generalized epilepsy with febrile seizures plus variants (4 disease-causing).
• Epilepsy is also caused by SCN1A variants; they fall mostly in different places as the Generalized epilepsy with febrile seizures plus variants (4 disease-causing).
• Primary erythromelalgia is also caused by SCN9A variants; they fall mostly in different places as the Generalized epilepsy with febrile seizures plus variants (6 disease-causing).
• Paroxysmal extreme pain disorder is also caused by SCN9A variants; they fall partly in the same places as the Generalized epilepsy with febrile seizures plus variants (4 disease-causing).
• Early-infantile DEE is also caused by HCN1 variants; they fall mostly in different places as the Generalized epilepsy with febrile seizures plus variants (14 disease-causing).

Diseases related to Generalized epilepsy with febrile seizures plus

• Epilepsy, also linked to GABRG2, SCN1A and SCN9A
• Genetic developmental and epileptic encephalopathy, also linked to GABRG2, HCN1 and SCN1A
• Lennox-Gastaut syndrome, also linked to GABRG2, SCN1A and SCN9A
• Early-infantile DEE, also linked to HCN1 and SCN1A
• Severe myoclonic epilepsy in infancy, also linked to HCN1 and SCN1A
• Amyotrophic lateral sclerosis, also linked to SCN1A and SCN9A
• Cardiac arrhythmia, also linked to SCN1A and SCN9A
• Febrile seizures, familial, 3a, also linked to GABRG2 and SCN1A
• Focal epilepsy, also linked to SCN1A and SCN9A
• EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2, also linked to GABRG2
• Migraine, familial hemiplegic, 1, also linked to SCN1A
• Neuropathy, hereditary sensory and autonomic, type 2A, also linked to SCN9A

Frequently asked questions

Which genes are linked to Generalized epilepsy with febrile seizures plus?

In CATVariant, Generalized epilepsy with febrile seizures plus is linked to 4 analyzed proteins: SCN1A (Sodium channel protein type 1 subunit alpha), SCN9A (Sodium channel protein type 9 subunit alpha), HCN1 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1) and GABRG2 (Gamma-aminobutyric acid receptor subunit gamma-2).

How many genetic variants are linked to Generalized epilepsy with febrile seizures plus?

1,456 variants: 100 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,297 are of uncertain significance or have conflicting reports.

Which uncertain variants in Generalized epilepsy with febrile seizures plus look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Generalized epilepsy with febrile seizures plus?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 75 disease-causing and 49 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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