Angelman syndrome: genes and variants

Genes linked to Angelman syndrome

• UBE3A: Ubiquitin-protein ligase E3A

  Its ubiquitin-ligase activity controls turnover of selected neuronal proteins and is subject to maternal-specific expression in many neurons. Loss of the maternal allele causes Angelman syndrome, while increased dosage contributes to neurodevelopmental abnormalities in 15q11-q13 duplication.

  14 disease-causing and 32 uncertain variants in UBE3A are linked to Angelman syndrome.

• CDKL5: Cyclin-dependent kinase-like 5

  It phosphorylates neuronal substrates involved in synapse development, cytoskeletal organization, and signaling during early brain maturation. Loss-of-function variants cause CDKL5 deficiency disorder with very early epilepsy and severe developmental impairment.

  0 disease-causing and 0 uncertain variants in CDKL5 are linked to Angelman syndrome.

• MECP2: Methyl-CpG-binding protein 2

  It interprets DNA methylation and organizes transcriptional and chromatin states that are especially important in mature neurons. Loss-of-function variants cause Rett syndrome, whereas increased dosage causes MECP2 duplication syndrome.

  0 disease-causing and 0 uncertain variants in MECP2 are linked to Angelman syndrome.

Where Angelman syndrome variants cluster

• UBE3A Interaction with HCV core protein (positions 418–517): 3 of 14 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Angelman syndrome

Which prediction tools work for Angelman syndrome

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

• MutPred2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 97 out of 100
• AlphaMissense: 95 out of 100
• PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 76 out of 100
• CATVariant: 69 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 51 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Angelman syndrome

• Rett syndrome, also linked to CDKL5 and MECP2
• Autism, also linked to CDKL5 and MECP2
• Angelman syndrome-like, also linked to CDKL5
• CDKL5 disorder, also linked to CDKL5
• Severe neonatal-onset encephalopathy with microcephaly, also linked to MECP2
• Focal epilepsy, also linked to MECP2
• Infantile spasms, also linked to CDKL5
• X-linked intellectual disability-psychosis-macroorchidism syndrome, also linked to MECP2
• Syndromic X-linked intellectual disability Lubs type, also linked to MECP2

Frequently asked questions

Which genes are linked to Angelman syndrome?

In CATVariant, Angelman syndrome is linked to 3 analyzed proteins: UBE3A (Ubiquitin-protein ligase E3A), CDKL5 (Cyclin-dependent kinase-like 5) and MECP2 (Methyl-CpG-binding protein 2).

How many genetic variants are linked to Angelman syndrome?

106 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 32 are of uncertain significance or have conflicting reports.

Which uncertain variants in Angelman syndrome 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 Angelman syndrome?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 13 disease-causing and 162 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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