VEXAS syndrome

Summary

VEXAS syndrome (MONDO:0026777) is a disease with 1 cohort gene and 8 clinical trials. Top therapeutic interventions include pacritinib and momelotinib.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 11
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		37	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	VEXAS syndrome
Mondo ID	MONDO:0026777
OMIM	301054
Orphanet	596753
DOID	DOID:0080828
NCIT	C181924
UMLS	C5435753
MedGen	1765785
GARD	0015001
Is cancer (heuristic)	no

Also known as: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome · VEXAS · VEXAS syndrome, somatic

Data availability: 11 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › VEXAS syndrome

Related subtypes (36): cherubism, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, psoriasis 14, pustular, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, periodic fever syndrome, infantile onset panniculitis with uveitis and systemic granulomatosis, idiopathic recurrent pericarditis, pyoderma gangrenosum-acne-suppurative hidradenitis syndrome, neonatal inflammatory skin and bowel disease, magic syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, Schnitzler syndrome, PFAPA syndrome, pyoderma gangrenosum, SAPHO syndrome, sarcoidosis, adult-onset Still disease, systemic-onset juvenile idiopathic arthritis, autoinflammatory syndrome, familial, Behcet-like, CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome, type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, early-onset pulmonary and cutaneous vasculitis, autoinflammatory syndrome due to TBK1 deficiency, F12-associated cold autoinflammatory syndrome, neonatal-onset severe multisystemic autoinflammatory disease with increased IL18, SAMD9L-associated autoinflammatory syndrome, autoinflammatory syndrome of childhood, autoinflammatory disease, systemic, with vasculitis, granulomatous autoinflammatory syndrome of childhood, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, PAPASH syndrome, Sharpin-related autoinflammatory syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
965290	NM_003334.4(UBA1):c.122T>C (p.Met41Thr)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
981654	NM_003334.4(UBA1):c.121A>C (p.Met41Leu)	LOC126863253	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1490238	NM_003334.4(UBA1):c.521G>A (p.Arg174Gln)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
836983	NM_003334.4(UBA1):c.121A>G (p.Met41Val)	UBA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298352	NM_003334.4(UBA1):c.167C>T (p.Ser56Phe)	LOC126863253	Uncertain significance	criteria provided, single submitter
1298353	NM_003334.4(UBA1):c.118-1G>C	LOC126863253	Uncertain significance	criteria provided, single submitter
1055089	NM_003334.4(UBA1):c.1147A>T (p.Ile383Phe)	UBA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1318833	NM_003334.4(UBA1):c.804A>T (p.Lys268Asn)	UBA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2901903	NM_003334.4(UBA1):c.2119G>A (p.Val707Met)	UBA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068023	NM_003334.4(UBA1):c.355C>T (p.Arg119Trp)	UBA1	Uncertain significance	criteria provided, single submitter
368339	NM_003334.4(UBA1):c.1702C>G (p.Leu568Val)	UBA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBA1	Orphanet:1145	Infantile-onset X-linked spinal muscular atrophy
UBA1	Orphanet:596753	VEXAS syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UBA1	HGNC:12469	ENSG00000130985	P22314	Ubiquitin-like modifier-activating enzyme 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBA1	Ubiquitin-like modifier-activating enzyme 1	Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UBA1	Enzyme (other)	yes	2.3.2.23	UBQ/SUMO-activ_enz_E1-like, ThiF_NAD_FAD-bd, UBQ-activ_enz_E1_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
pharyngeal mucosa	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBA1	292	ubiquitous	marker	endometrium epithelium, renal medulla, pharyngeal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBA1	4,870

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBA1	P22314	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.006	UBA1
Dengue Virus Attachment and Entry	1	259.6×	0.006	UBA1
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	UBA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ubiquitin-dependent protein catabolic process	1	74.2×	0.024	UBA1
DNA damage response	1	53.5×	0.024	UBA1
protein ubiquitination	1	41.4×	0.024	UBA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UBA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
UBA1	38	Binding:38

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBA1	2.3.2.23, 6.2.1.45, 6.2.1.64	E2 ubiquitin-conjugating enzyme, E1 ubiquitin-activating enzyme, E1 NEDD8-activating enzyme

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	UBA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
UBA1	38	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2/PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07569081	PHASE2/PHASE3	NOT_YET_RECRUITING	A Study Evaluating the Efficacy and Safety of Momelotinib in Participants With Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome
NCT06782373	PHASE2	RECRUITING	A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)
NCT06538181	PHASE1	RECRUITING	Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome
NCT05200715	Not specified	RECRUITING	AutoInflammatory Disease Alliance Registry (AIDA)
NCT05969821	Not specified	NOT_YET_RECRUITING	Clonal Hematopoiesis of Immunological Significance
NCT06377462	Not specified	RECRUITING	Multicenter, Interdisciplinary National VEXAS Registry With Accompanying Biomaterial Collection
NCT06657846	Not specified	RECRUITING	HRQoL and Financial Toxicity in Patients With VEXAS Syndrome
NCT07102849	Not specified	ENROLLING_BY_INVITATION	Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PACRITINIB	4	2
MOMELOTINIB	4	1
CHEMBL4778465	0	2