UBA1

Chr XXLR

ubiquitin like modifier activating enzyme 1

Also known as: A1S9, A1S9T, A1ST, AMCX1, CFAP124, GXP1, POC20, SMAX2

NCBI Gene: 7317ENSG00000130985UniProt: P22314OMIM: 314370

This X-linked gene encodes the E1 ubiquitin-activating enzyme that catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation and plays an essential role in DNA repair. Mutations cause X-linked spinal muscular atrophy type 2 with infantile onset and VEXAS syndrome (somatic mutations), following X-linked recessive inheritance for the germline condition. The gene is highly constrained against loss-of-function variants, indicating that such variants are likely to be pathogenic.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismXLRLOEUF 0.112 OMIM phenotypes
Clinical Summary— UBA1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
21 unique Pathogenic / Likely Pathogenic· 180 VUS of 500 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — UBA1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.11LOEUF
pLI 1.000
Z-score 6.01
OE 0.02 (0.01–0.11)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
3.48Z-score
OE missense 0.54 (0.49–0.60)
248 obs / 457.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.02 (0.01–0.11)
0≤0.351.4
Missense OE0.54 (0.49–0.60)
0≤0.61.4
Synonymous OE1.11
0≤1.21.6
LoF obs/exp: 1 / 44.1Missense obs/exp: 248 / 457.1Syn Z: -1.14
DN
0.2399th %ile
GOF
0.3590th %ile
LOF
0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.11

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic1
VUS180
Likely Benign145
Benign25
Conflicting3
20
Pathogenic
1
Likely Pathogenic
180
VUS
145
Likely Benign
25
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
0
1
0
1
VUS
1
154
20
5
180
Likely Benign
0
8
69
68
145
Benign
0
5
14
6
25
Conflicting
—3
Total116712479374

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

View in ClinVar →

Protein Context — Lollipop Plot

UBA1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
VEXAS syndrome: Clinical manifestations, diagnosis, and treatment.
Loeza-Uribe MP et al.·Reumatol Clin (Engl Ed)
2024Review
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.
Beck DB et al.·N Engl J Med
2020
An update on VEXAS syndrome.
Al-Hakim A et al.·Expert Rev Clin Immunol
2023Review
VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management.
Koster MJ et al.·Am J Hematol
2024Review
VEXAS syndrome.
Nakajima H et al.·Int J Hematol
2025Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients