UBE3C

Chr 7AR

ubiquitin protein ligase E3C

Also known as: HECTH2, NDSMBA, NEDSMBA, RAUL

NCBI Gene: 9690ENSG00000009335UniProt: Q15386

Enables ubiquitin protein ligase activity. Involved in protein K29-linked ubiquitination; protein K48-linked ubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to be part of proteasome complex. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with absent speech and movement and behavioral abnormalitiesMIM #620270
AR
255
ClinVar variants
88
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— UBE3C
⚡
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.
📋
ClinVar Variants
88 Pathogenic / Likely Pathogenic· 116 VUS of 255 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.18LOEUF
pLI 1.000
Z-score 6.41
OE 0.09 (0.04–0.18)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.54Z-score
OE missense 0.71 (0.65–0.77)
421 obs / 595.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.65–0.77)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 5 / 57.4Missense obs/exp: 421 / 595.8Syn Z: 0.80

ClinVar Variant Classifications

255 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic80
Likely Pathogenic8
VUS116
Likely Benign11
Benign3
80
Pathogenic
8
Likely Pathogenic
116
VUS
11
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
80
0
80
Likely Pathogenic
1
0
7
0
8
VUS
0
108
8
0
116
Likely Benign
0
3
1
7
11
Benign
0
0
1
2
3
Total1111979218

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

View in ClinVar →

Protein Context — Lollipop Plot

UBE3C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

UBE3C-related neurodevelopmental disorder with absent speech and movement and behavioural abnormalities

limited
ARUndeterminedAbsent Gene Product
Dev. Disorders
G2P ↗
frameshift variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities

MIM #620270

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.
Faqeih EA et al.·Genet Med
2023
SEC61G Facilitates Brain Metastases via Antagonizing PGAM1 Ubiquitination and Immune Microenvironment Remodeling in Non-Small Cell Lung Cancer.
Zhou C et al.·Int J Biol Sci
2025Functional
UBE3C promotes pancreatic ductal adenocarcinoma progression by catalysing p53 ubiquitination.
Shi Y et al.·Mol Biol Rep
2025
Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy.
Cutrupi AN et al.·Brain
2023
Identification of UBE3C as an E3 ubiquitin ligase for mutant BRAF.
Kim DY et al.·Life Sci
2025
Ubiquitin-protein ligase E3C maintains non-small-cell lung cancer stemness by targeting AHNAK-p53 complex.
Gu J et al.·Cancer Lett
2019
Exploring the "Other" subfamily of HECT E3-ligases for therapeutic intervention.
Singh S et al.·Pharmacol Ther
2021Review
UBE3C promotes proliferation and inhibits apoptosis by activating the β-catenin signaling via degradation of AXIN1 in gastric cancer.
Zhang Y et al.·Carcinogenesis
2021
Association analysis of UBE3C polymorphisms in Korean aspirin-intolerant asthmatic patients.
Lee JS et al.·Ann Allergy Asthma Immunol
2010Cohort
Ubiquitin-proteasome Pathway-linked Gene Signatures as Prognostic Indicators in Prostate Cancer.
Takashima Y et al.·Anticancer Res
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools