UBE2A

Chr XXLR

ubiquitin conjugating enzyme E2 A

Also known as: HHR6A, MRXS30, MRXSN, RAD6A, UBC2

NCBI Gene: 7319ENSG00000077721UniProt: P49459

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Nascimento typeMIM #300860
XLR
168
ClinVar variants
97
Pathogenic / LP
0.82
pLI score
0
Active trials
Clinical Summary— UBE2A
🧬
Gene-Disease Validity (ClinGen)
syndromic X-linked intellectual disability Nascimento type · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.82) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 48 VUS of 168 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.54LOEUF
pLI 0.815
Z-score 2.19
OE 0.00 (0.00–0.54)
Moderately constrained

More LoF-intolerant than ~75% 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.
2.46Z-score
OE missense 0.13 (0.07–0.23)
8 obs / 63.0 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.0.00 (0.00–0.54)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.13 (0.07–0.23)
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.0.89
0≤1.21.6
LoF obs/exp: 0 / 5.6Missense obs/exp: 8 / 63.0Syn Z: 0.38

ClinVar Variant Classifications

168 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic85
Likely Pathogenic12
VUS48
Likely Benign20
Benign2
Conflicting1
85
Pathogenic
12
Likely Pathogenic
48
VUS
20
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
80
0
85
Likely Pathogenic
6
3
3
0
12
VUS
2
27
18
1
48
Likely Benign
0
1
9
10
20
Benign
0
0
2
0
2
Conflicting
—1
Total113311211168

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

View in ClinVar →

Protein Context — Lollipop Plot

UBE2A · protein map & ClinVar variants

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

Gene2Phenotype Curations

UBE2A-related syndromic intellectual developmental disorder

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, Nascimento type

MIM #300860

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome.
Cordeddu V et al.·Clin Genet
2020
UBE2A-related X-linked intellectual disability.
Stevenson RE et al.·Clin Dysmorphol
2019Case report
Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability.
de Oliveira JF et al.·Nat Chem Biol
2019
UBE2A deficiency syndrome: a report of two unrelated cases with large Xq24 deletions encompassing UBE2A gene.
Thunstrom S et al.·Am J Med Genet A
2015Case report
[A large family of Nascimento form of syndromic X-linked intellectual developmental disorder caused by large segment deletion of the UBE2A gene: a case report and literature review].
Xu D et al.·Zhongguo Dang Dai Er Ke Za Zhi
2025Review
Next-generation sequencing in X-linked intellectual disability.
Tzschach A et al.·Eur J Hum Genet
2015
Sudden infant death in a neonate with X-linked intellectual disability type Nascimento because of UBE2A deletion.
Furtado Gomes I et al.·Clin Dysmorphol
2025Case report
UBE2A deficiency in two siblings: A novel splicing variant inherited from a maternal germline mosaicism.
Giugliano T et al.·Am J Med Genet A
2018Case report
Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome.
Budny B et al.·Clin Genet
2010
X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity.
Czeschik JC et al.·Orphanet J Rare Dis
2013
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