UBA2

protein-coding

ubiquitin like modifier activating enzyme 2, the group of Ubiquitin like modifier activating enzymes

Gene summary

Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1; MIM 601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 (MIM 613294) and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999 [PubMed 9920803]).[supplied by OMIM, Mar 2010]

Previous symbols:

SAE2

MANE transcript

NM_005499.3

Inheritance

ClinVar variants

P:31U:89B:5

Top phenotype

ACCES syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr19:34,428,352-34,471,251

External References & Databases

Ensembl (ENSG00000126261)

Transcript & Mutation Effects

hg38 • Region Span ~42.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ACCES syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859262

Submitter: Labcorp Genetics (formerly Invitae)

ACCES syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859262

Submitter: PanelApp Australia

ACCES syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859262

Submitter: ClinGen

The *UBA2* gene, located on chromosome 19 at 19q13.11, encodes a ubiquitin-like modifier activating enzyme that forms a heterodimer with SAE1 and binds to SUMO proteins, initiating SUMOylation (post-translational protein-modification similar to ubiquitination). *UBA2* was first reported in relation to autosomal dominant ACCES syndrome in 2017 (Marble et al. PMID: 28110515). ACCES syndrome is characterized by aplasia cutis congenita (ACC), limb anomalies, early growth deficiency, developmental delay, with clinical heterogeneity. Additionally, UBA2 has been identified as a driver of the ACC phenotype in 19q13.11 microdeletion syndrome (Abe et al. 2018, PMID: 29988626). Eight unique variants, including seven truncating and one missense, that have been reported in 8 families across six publications (PMID: 28110515; Yamamoto et al. 2019, PMID: 31332306; Wang et al. 2020, PMID: 31587267; Aerden et al. 2020, PMID: 32758660; Schnur et al. 2021, PMID: 34040189; Elsner et al. 2021, PMID: 34159400) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a zebrafish model (PMID: 34040189). In summary, there is definitive evidence supporting the relationship between *UBA2* and autosomal dominant ACCES syndrome. 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 Syndromic Disorders GCEP on the meeting date September 4, 2024 (SOP Version 10).

ACCES syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859262

Submitter: G2P

multiple congenital anomalies/dysmorphic syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

ACCES syndromeAD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can include congenital cardiac anomalies, and awareness may allow early identification and management

Refs: 34040189

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBA2 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 59

not providedTotal: 32

ACCES syndromeTotal: 26

UBA2-related disorderTotal: 5

EctrodactylyTotal: 1

UBA2-related neurodevelopmental disorder with multiple anomaliesTotal: 1

Chromosome 19q13.11 deletion syndrome, distalTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005499.3. 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			2 clinvar	3 clinvar		5
missense		5 clinvar	81 clinvar	2 clinvar		88
nonsense	2 clinvar	3 clinvar				5
start loss		1 clinvar				1
frameshift	10 clinvar	5 clinvar	2 clinvar			17
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar	4 clinvar			9
Total	15	16	89	5	0	125

Highest pathogenic variant AF is 0.0000034539546

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005499.3	RefSeq	NP_005490.1	17	MANE Select
ENST00000246548.9	Ensembl	ENSP00000246548.3	17	MANE Select
NM_001411139.1	RefSeq	NP_001398068.1	15	Standard
ENST00000439527.6	Ensembl	ENSP00000437484.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
SUMO is conjugated to E1 (UBA2:SAE1)
SUMO is transferred from E1 to E2 (UBE2I, UBC9)
Post-translational protein modification
basic mechanisms of sumoylation

Biological Process

protein sumoylation
protein modification by small protein conjugation
positive regulation of catalytic activity

Molecular Function

magnesium ion binding
protein binding
ATP binding
enzyme activator activity
transcription factor binding

Cellular Component

nucleoplasm
cytoplasm
SUMO activating enzyme complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246548
Coding exons: 17
Length: 41597
Individuals with no LoFs: 122449
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 122450
p: 0.00000408

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.61	190	322	0.591	0.0000166	4220
Missense (PolyPhen)		17	77.479	0.21941		1080
Synonymous	0.543	106	113	0.935	0.00000612	1182
Loss of Function	4.77	3	32.2	0.0932	0.00000152	427

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000031	0.000031	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2. {ECO:0000269|PubMed:11451954, ECO:0000269|PubMed:11481243, ECO:0000269|PubMed:15660128, ECO:0000269|PubMed:17643372, ECO:0000269|PubMed:19443651, ECO:0000269|PubMed:20164921}.;

Recessive Scores

pRec: 0.136

Intolerance Scores

LoFtool: 0.0661
RVIS EVS: -0.25
RVIS percentile EVS: 35.99

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.815

Gene Damage Prediction

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