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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

296 unique Pathogenic / Likely Pathogenic· 417 VUS of 1071 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — UBE3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.08 (0.04–0.21)

0≤0.351.4

Missense OE?0.42 (0.37–0.47)

0≤0.61.4

Synonymous OE?0.95

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

This gene — mechanism propensity

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 · 71% of P/LP variants are LoF · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

LOFA novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree2

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

References

ClinVar Variant Classifications

1071 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic204

Likely Pathogenic92

VUS417

Likely Benign275

Benign47

Conflicting17

204

Pathogenic

Likely Pathogenic

417

VUS

275

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	166	22	16	0	204
Likely Pathogenic	43	49	0	0	92
VUS	3	374	33	7	417
Likely Benign	3	3	87	182	275
Benign	0	5	29	13	47
Conflicting	—				17
Total	215	453	165	202	1,052

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

321 pathogenic / likely-pathogenic (of 335) ClinVar copy-number / structural variants overlap UBE3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →