Human Gene Module / Chromosome 8 / UBR5

UBR5ubiquitin protein ligase E3 component n-recognin 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 13
Rare Variants / Common Variants
43 / 0
EAGLE Score
18.45
Strong Learn More
Aliases
UBR5, DD5,  EDD,  EDD1,  HYD
Associated Syndromes
-
Chromosome Band
8q22.3
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

A de novo frameshift variant in the UBR5 gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25961944). A missense mutation in the UBR5 gene was detected in all affected individuals of a Japanese pedigree (6 affected individuals through 4 generations) with familial adult myoclonic epilepsy, but not in any non-affected family members; this variant was also not detected in 85 unrelated healthy residents of the pedigree's community, nor in 24 control individuals of various ethnicities (Kato et al., 2012). More recently, Sabeh et al., 2024 reported UBR5 variants in 29 unrelated individuals presenting with a neurodevelopmental syndrome characterized by developmental delay, autism or autistic features, intellectual disability, epilepsy, movement disorders, and/or genital anomalies; decreased ubiquitination activity was observed in several UBR5 variants described in this report.

Molecular Function

This gene encodes a progestin-induced protein, which belongs to the HECT (homology to E6-AP carboxyl terminus) family. The HECT family proteins function as E3 ubiquitin-protein ligases, targeting specific proteins for ubiquitin-mediated proteolysis. This gene potentially has a role in regulation of cell proliferation or differentiation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to UBR5 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family Kato T , et al. (2012) No -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support - Qaiser F et al. (2021) Yes -
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Marta Viggiano et al. (2024) Yes ID
13 Recent Recommendation - Pascale Sabeh et al. (2025) No ASD or autistic features, ADHD, ID, epilepsy/seizu
Rare Variants   (43)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5026A>G p.Ser1676Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3925C>T p.Pro1309Ser missense_variant De novo - - 34622207 Qaiser F et al. (2021)
c.331C>T p.Pro111Ser missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1484G>A p.Gly495Asp missense_variant Unknown - - 39721588 Pascale Sabeh et al. (2025)
c.245dup p.Lys83Ter stop_gained De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.7843-11A>G p.? intron_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.4916G>C p.Arg1639Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4812G>A p.Glu1604= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8303G>A p.Cys2768Tyr missense_variant De novo - - 39721588 Pascale Sabeh et al. (2025)
c.8304C>G p.Cys2768Trp missense_variant De novo - - 39721588 Pascale Sabeh et al. (2025)
c.4049A>C p.Asn1350Thr missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1897C>T p.Arg633Ter stop_gained De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.62+1G>A p.? splice_site_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.381C>T p.Thr127= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7924A>T p.Arg2642Ter stop_gained De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.752_753del p.Leu251ProfsTer2 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.4957+1G>A p.? splice_site_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.2591C>G p.Ala864Gly missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.455G>C p.Arg152Pro missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.734G>C p.Gly245Ala missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.7336A>G p.Met2446Val missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1447A>G p.Thr483Ala missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.2054C>T p.Thr685Ile missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.3682C>T p.Pro1228Ser missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.4148T>C p.Phe1383Ser missense_variant Unknown - Simplex 39721588 Pascale Sabeh et al. (2025)
c.4598A>G p.Gln1533Arg missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.4919G>C p.Arg1640Thr missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.5074G>A p.Asp1692Asn missense_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.752_753del p.Leu251ProfsTer2 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.7686+3_7686+6del p.? splice_site_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.6672dup p.Phe2225IlefsTer21 frameshift_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3622_3624del p.Cys1208del inframe_deletion De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.5746G>A p.Asp1916Asn missense_variant Familial - Multi-generational 23029623 Kato T , et al. (2012)
c.7444G>A p.Gly2482Ser missense_variant Familial Both parents - 39721588 Pascale Sabeh et al. (2025)
c.4776_4777del p.Glu1593ArgfsTer4 frameshift_variant De novo - - 39721588 Pascale Sabeh et al. (2025)
c.4447_4450del p.Ile1483PhefsTer21 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4141del p.Asp1381ThrfsTer8 frameshift_variant De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.5749T>C p.Phe1917Leu missense_variant Familial Maternal Simplex 39721588 Pascale Sabeh et al. (2025)
c.7441del p.His2481MetfsTer7 frameshift_variant De novo - Multiplex 38519481 Marta Viggiano et al. (2024)
c.6557_6562del p.Leu2186_Gly2187del inframe_deletion De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.1624del p.Tyr542IlefsTer20 frameshift_variant Familial Maternal Simplex 39721588 Pascale Sabeh et al. (2025)
c.4136_4141dup p.Leu1380_Asp1381insGlyLeu inframe_insertion De novo - Simplex 39721588 Pascale Sabeh et al. (2025)
c.4908T>C p.Ala1636= synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in UBR5 was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.01) (PMID 25961944). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo LoF variant in UBR5 was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.01) (PMID 25961944). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in UBR5 was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.01) (PMID 25961944). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in UBR5 was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.01) (PMID 25961944). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
1/1/2016
icon
3

Increased from to 3

Description

A de novo LoF variant in UBR5 was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.01) (PMID 25961944). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
Krishnan Probability Score

Score 0.53010352797764

Ranking 1553/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 1

Ranking 8/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.976

Ranking 49/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.73999452056851

Ranking 1460/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.15992014009928

Ranking 4979/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CALR3 Calreticulin-3 Human Protein Binding 125972 Q96L12
PRSS37 Probable inactive serine protease 37 Human Protein Binding 136242 A4D1T9
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