UBE3A

Chr 15AD

ubiquitin protein ligase E3A

Also known as: ANCR, AS, E6-AP, EPVE6AP, HPVE6A, PIX1

NCBI Gene: 7337 ENSG00000114062 UniProt: Q05086 OMIM: 601623

This gene encodes an E3 ubiquitin-protein ligase that targets proteins for degradation and is maternally expressed in brain tissue due to genomic imprinting. Maternal deletions or loss-of-function mutations cause Angelman syndrome, characterized by severe intellectual disability, motor developmental delay, ataxia, hypotonia, epilepsy, absent speech, and distinctive facial features. The gene shows extreme intolerance to loss-of-function variants (pLI 0.99), consistent with haploinsufficiency as the predominant disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.211 OMIM phenotype

VCEP Guidelines: Rett/Angelman-like DisordersReleased

View Specifications ClinGen Panel

Clinical Summary— UBE3A

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Gene-Disease Validity (ClinGen)

Angelman syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.21LOEUF

pLI 1.000

Z-score 5.23

OE 0.08 (0.04–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.40Z-score

OE missense 0.42 (0.37–0.47)

191 obs / 455.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.08 (0.04–0.21)

0≤0.351.4

Missense OE0.42 (0.37–0.47)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 3 / 37.6Missense obs/exp: 191 / 455.4Syn Z: 0.51

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveUBE3A-related Angelman syndromeLOFAD

0.2997th %ile

GOF

0.4874th %ile

LOF

0.70top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.21

GOF1 literature citation

Literature Evidence

GOFInterestingly, duplication, triplication, or gain-of-function mutations in the UBE3A gene are also linked with autism clinically distinguished by social impairments and stereotyped behaviors.PMID:30568575

LOFA novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigreePMID:20034088

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.