UBA5

protein-coding

ubiquitin like modifier activating enzyme 5, the group of Ubiquitin like modifier activating enzymes

Gene summary

This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1. [provided by RefSeq, Feb 2016]

Previous symbols:

UBE1DC1

MANE transcript

NM_024818.6

Inheritance

AR, AD

ClinVar variants

P:45U:106B:66

Top phenotype

Developmental and epileptic encephalopathy 44; Spinocerebellar ataxia, autosomal recessive 24

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr3:132,654,446-132,679,794

External References & Databases

Ensembl (ENSG00000081307)

Transcript & Mutation Effects

hg38 • Region Span ~25.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia, autosomal recessive 24MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014934

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014933

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

*UBA5* was first reported with an autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 (Muona 2016, PMID: 27545674 and Colin 2016, PMID: 27545681). Currently, at least 38 individuals have been reported with *UBA5*-related DEE. The majority of reported individuals have early-onset encephalopathy with or without seizures, abnormal tone, movement abnormalities, severe global delay, intellectual disability, visual impairment, acquired microcephaly, and significant failure to thrive. However, two siblings with a progressive childhood-onset cerebellar ataxia with normal intellect were also reported to have a missense and nonsense *UBA5* variant *in trans* (Duan 2016, PMID: 26872069). Additionally, five individuals from a large consanguineous family had a severe congenital neuropathy that resulted in death in early infancy due to respiratory failure and carried a homozygous missense variant with significantly decreased activity (Cabrera-Serrano 2020, PMID: 32179706). These cases were not curated for DEE. These two families may suggest a wider phenotypic spectrum of *UBA5*-related DEE, which may depend on the functional activity and location of the *UBA5* variants detected. Therefore, we have split this curation into two disease entities; this curation represents the relationship between *UBA5* and autosomal recessive DEE only, with additional studies needed to determine the complete genotype-phenotype spectrum for *UBA5*-related DEE. Ten missense, four nonsense, one frameshift, and two whole gene deletions reported in sixteen probands across six publications (PMIDs: 27545674, 27545681, 33811063, 29902590, 30078785, and 40217280) were included in this curation. A recurrent hypomorphic variant (NM_024818.6:c.1111G>A, p.Ala371Thr) has been reported in the compound heterozygous state in several of these individuals (PMIDs: 27545674, 27545681, and 33811063). Additional evidence is available in the literature beyond what is referenced here; however, the maximum score for genetic and experimental evidence has been reached. The mechanism of pathogenicity is loss of function (PMIDs: 27545674, 27545681, and 33811063). Functional studies of these variants show that affected individuals have a loss-of-function variant *in* *trans* with a variant that has some functional activity, suggesting that inheritance of two fully non-functional variants is lethal. This is supported by knockout animal models that do not survive (not scored, PMIDs: 21304510, 27545681, and 26872069). In summary, there is definitive evidence to support the relationship between *UBA5* and autosomal recessive developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 5, 2025 (SOP version 11).

developmental and epileptic encephalopathy, 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014933

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

spinocerebellar ataxia, autosomal recessive 24LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014934

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 44DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014933

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 44; Spinocerebellar ataxia, autosomal recessive 24AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26872069; 27545674; 27545681

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBA5 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 229

Inborn genetic diseasesTotal: 37

Developmental and epileptic encephalopathy, 44Total: 36

UBA5-related disorderTotal: 10

Spinocerebellar ataxia, autosomal recessive 24Total: 8

not specifiedTotal: 2

Developmental and epileptic encephalopathyTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024818.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	2 clinvar	63 clinvar		66
missense	4 clinvar	14 clinvar	102 clinvar	2 clinvar	1 clinvar	123
nonsense	3 clinvar	4 clinvar				7
start loss	1 clinvar					1
frameshift	13 clinvar	2 clinvar	1 clinvar			16
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	1 clinvar			4
Total	22	23	106	65	1	217

Highest pathogenic variant AF is 0.0026954683

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024818.6	RefSeq	NP_079094.1	12	MANE Select
ENST00000356232.10	Ensembl	ENSP00000348565.4	12	MANE Select
NM_001320210.2	RefSeq	NP_001307139.1	11	Standard
NM_001321238.2	RefSeq	NP_001308167.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
uba5	Danio rerio	Structure: whole organism Quality: decreased mobility abnormal

Gene / Model

Organism

Observed Phenotype

uba5

Danio rerio

Structure: whole organism

Quality: decreased mobility

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

protein ubiquitylation
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

protein modification by small protein conjugation
regulation of intracellular estrogen receptor signaling pathway
response to endoplasmic reticulum stress
neuromuscular process
protein ufmylation

Molecular Function

protein binding
ATP binding
metal ion binding
UFM1 activating enzyme activity

Cellular Component

nucleus
cytoplasm
Golgi apparatus
cytosol
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356232
Coding exons: 12
Length: 23652
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125723
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	158	211	0.750	0.00000988	2659
Missense (PolyPhen)		24	51.682	0.46438		630
Synonymous	1.52	54	70.2	0.769	0.00000331	749
Loss of Function	2.58	10	23.5	0.426	0.00000126	277

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E1-like enzyme which activates UFM1 and SUMO2. {ECO:0000269|PubMed:15071506, ECO:0000269|PubMed:18442052, ECO:0000269|PubMed:20368332, ECO:0000269|PubMed:27545674, ECO:0000269|PubMed:27545681}.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 24 (SCAR24) [MIM:617133]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR24 patients manifest gait instability and speech difficulties with onset in childhood. Clinical features include gait and limb ataxia, dysarthria, nystagmus, cataracts, and cerebellar atrophy on brain imaging. {ECO:0000269|PubMed:26872069}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0887

Intolerance Scores

LoFtool: 0.418
RVIS EVS: 0.17
RVIS percentile EVS: 65.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.735

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium