UBE2A

protein-coding

ubiquitin conjugating enzyme E2 A, the group of Ubiquitin conjugating enzymes E2

Gene summary

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is required for post-replicative DNA damage repair, and may play a role in transcriptional regulation. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

MANE transcript

NM_003336.4

Inheritance

ClinVar variants

P:20U:54B:12

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, Nascimento-type

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:119,474,802-119,591,083

External References & Databases

Ensembl (ENSG00000077721)

Transcript & Mutation Effects

hg38 • Region Span ~116.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic X-linked intellectual disability Nascimento typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: G2P

syndromic X-linked intellectual disability Nascimento typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: Orphanet

syndromic X-linked intellectual disability Nascimento typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: PanelApp Australia

syndromic X-linked intellectual disability Nascimento typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: Labcorp Genetics (formerly Invitae)

syndromic X-linked intellectual disability Nascimento typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: ClinGen

*UBE2A* encodes an E2 ubiquitin-conjugating enzyme involved in the ubiquitin proteasome pathway of protein degradation. *UBE2A* was first reported in relation to syndromic X-linked intellectual disability Nascimento type, also known as *UBE2A* deficiency syndrome, in 2006 (Nascimento et al., PMID: 16909393). In males, the syndrome is characterized by developmental delay, mild to severe intellectual disability, speech impairment, seizures, dysmorphic features (synophrys, prominent supraorbital ridges, deep almond-shaped eyes and wide mouth), hirsutism, micropenis, and digit and foot anomalies. Other features may include congenital heart defects and pineal gland tumors. Female carriers have normal cognition, but may show subtle facial features. In addition to sequence variants, Xq24 deletions involving *UBE2A* are associated with intellectual disability with overlapping phenotypes. Ten variants (missense, nonsense, frameshift, splice-site and large intragenic deletion) that have been reported in 10 probands in 6 publications (PMIDs: 16909393, 20412111, 23685073, 24053514, 28611923, 29283210) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The syndrome is associated with familial and *de novo* inheritance. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by biochemical function in the ubiquitin proteasome pathway and by animal models. In summary, there is definitive evidence supporting the relationship between *UBE2A* and syndromic X-linked intellectual disability Nascimento type. 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 2, 2018 (SOP Version 5). As of February 2026, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 12. No new evidence was added, and the classification remains the same.

syndromic X-linked intellectual disability Nascimento typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010461

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, Nascimento-typeXL

Manifestation: Craniofacial; Dermatologic; Genitourinary; Musculoskeletal; 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: 16909393; 20339384; 20412111; 21108393

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBE2A variants in ClinVar

7 Conditions Cataloged

not providedTotal: 42

Syndromic X-linked intellectual disability Nascimento typeTotal: 23

Inborn genetic diseasesTotal: 14

not specifiedTotal: 6

UBE2A-related disorderTotal: 2

Neurodevelopmental delayTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003336.4. 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			3 clinvar	11 clinvar		14
missense	3 clinvar	2 clinvar	35 clinvar	1 clinvar		41
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss		2 clinvar				2
frameshift		3 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	13 clinvar			20
Total	8	12	54	12	0	86

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003336.4	RefSeq	NP_003327.2	6	MANE Select
ENST00000371558.7	Ensembl	ENSP00000360613.2	6	MANE Select
NM_001282161.2	RefSeq	NP_001269090.1	5	Standard
NM_181762.3	RefSeq	NP_861427.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
hypoxia-inducible factor in the cardivascular system
hypoxia and p53 in the cardiovascular system
tumor suppressor arf inhibits ribosomal biogenesis
proteasome complex

Biological Process

protein polyubiquitination
blastocyst hatching
DNA repair
postreplication repair
ubiquitin-dependent protein catabolic process

Molecular Function

ubiquitin-protein transferase activity
protein binding
ATP binding
ubiquitin protein ligase binding
ubiquitin binding

Cellular Component

chromatin
nuclear chromatin
XY body
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371558
Coding exons: 6
Length: 9881
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.46	8	63.0	0.127	0.00000468	1005
Missense (PolyPhen)		2	25.935	0.077116		460
Synonymous	0.384	18	20.2	0.891	0.00000131	282
Loss of Function	2.19	0	5.57	0.00	3.53e-7	95

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
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: Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In association with the E3 enzyme BRE1 (RNF20 and/or RNF40), it plays a role in transcription regulation by catalyzing the monoubiquitination of histone H2B at 'Lys-120' to form H2BK120ub1. H2BK120ub1 gives a specific tag for epigenetic transcriptional activation, elongation by RNA polymerase II, telomeric silencing, and is also a prerequisite for H3K4me and H3K79me formation. In vitro catalyzes 'Lys-11', as well as 'Lys-48'-linked polyubiquitination. Required for postreplication repair of UV-damaged DNA. {ECO:0000269|PubMed:16337599, ECO:0000269|PubMed:20061386}.;
Disease: DISEASE: Mental retardation, X-linked, syndromic, Nascimento-type (MRXSN) [MIM:300860]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSN features include dysmorphic facies, hirsutism, skin and nails abnormalities, obesity, speech anomalies and seizures. {ECO:0000269|PubMed:16909393, ECO:0000269|PubMed:20412111}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Intolerance Scores

RVIS EVS: 0.15
RVIS percentile EVS: 63.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973