ASXL1

Chr 20AD

ASXL transcriptional regulator 1

NCBI Gene: 171023ENSG00000171456UniProt: Q8IXJ9

Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:16606617). Acts as a coactivator of RARA and RXRA through association with NCOA1 (PubMed:16606617). Acts as a corepressor for PPARG and suppresses its adipocyte differentiation-inducing activity (By similarity). Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459, PubMed:30664650, PubMed:36180891). Acts as a sensor of N(6)-methyladenine methylation on DNA (6mA): recognizes and binds 6mA DNA, leading to its ubiquitination and degradation by TRIP12, thereby inactivating the PR-DUB complex and regulating Polycomb silencing (PubMed:30982744). The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability (PubMed:30664650, PubMed:36180891). ASXL1, ASXL2 and ASXL3 function redundantly in the PR-DUB complex (By similarity) (PubMed:30664650). The ASXL proteins are essential for chromatin recruitment and transcriptional activation of associated genes (By similarity). ASXL1 and ASXL2 are important for BAP1 protein stability (PubMed:30664650). Together with BAP1, negatively regulates epithelial-mesenchymal transition (EMT) of trophoblast stem cells during placental development by regulating genes involved in epithelial cell integrity, cell adhesion and cytoskeletal organization (PubMed:34170818)

Primary Disease Associations & Inheritance

Bohring-Opitz syndromeMIM #605039
AD
Myelodysplastic syndrome, somaticMIM #614286
587
ClinVar variants
11
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— ASXL1
🧬
Gene-Disease Validity (ClinGen)
Bohring-Opitz syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 365 VUS of 587 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.79LOEUF
pLI 0.000
Z-score 2.77
OE 0.59 (0.44–0.79)
Tolerant

Typical tolerance to LoF variation

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.
0.64Z-score
OE missense 0.94 (0.88–0.99)
791 obs / 842.9 exp
Tolerant

Mild missense constraint

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.0.59 (0.44–0.79)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.88–0.99)
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.1.03
0≤1.21.6
LoF obs/exp: 31 / 52.7Missense obs/exp: 791 / 842.9Syn Z: -0.42

ClinVar Variant Classifications

587 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic7
VUS365
Likely Benign209
Conflicting2
4
Pathogenic
7
Likely Pathogenic
365
VUS
209
Likely Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
4
0
3
0
7
VUS
0
363
2
0
365
Likely Benign
0
32
4
173
209
Benign
0
0
0
0
0
Conflicting
—2
Total439513173587

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

View in ClinVar →

Protein Context — Lollipop Plot

ASXL1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ASXL1-related Bohring-Opitz syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Bohring-Opitz syndrome

MIM #605039

Molecular basis of disorder known

Autosomal dominant

Myelodysplastic syndrome, somatic

MIM #614286

Molecular basis of disorder known

📖
GeneReview available — ASXL1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.
Patnaik MM et al.·Hematology Am Soc Hematol Educ Program
2020Review
The spectrum of GATA2 deficiency syndrome.
Calvo KR et al.·Blood
2023
Progression in Myeloid Neoplasms: Beyond the Myeloblast.
Faria C et al.·Pathobiology
2024Review
Genomics of Acute Myeloid Leukemia Diagnosis and Pathways.
Bullinger L et al.·J Clin Oncol
2017Review
A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets.
Vlasschaert C et al.·Blood
2023
Cancer therapy shapes the fitness landscape of clonal hematopoiesis.
Bolton KL et al.·Nat Genet
2020
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
Yoshizato T et al.·N Engl J Med
2015
Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.
Bataller A et al.·Am J Hematol
2023Cohort
Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.
Sirenko M et al.·Blood
2024
Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms.
Palomo L et al.·Blood
2020
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
Diffuse Large B Cell Lymphoma

Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

RECRUITING
NCT06161896Lars Møller PedersenStarted 2024-05-06
Stool samples
Myeloproliferative Neoplasm

Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

RECRUITING
NCT06022328University Hospital, BordeauxStarted 2023-12-15
Assessment of the epigenetic age
AMLMDS

Molecular Genetics Guide the Maintenance Therapy After Allogeneic Hematopoietic Stem Cell Transplantation

RECRUITING
NCT06972641Phase PHASE2, PHASE3Ruijin HospitalStarted 2025-06-10
DecitabineSorafenib (BAY-43-9006)，giritinibAvastinib
Bohring-Opitz SyndromeASXL1 Gene MutationShashi-Pena Syndrome

ASXL-Related Disorders Natural History Study

RECRUITING
NCT03303716University of California, Los AngelesStarted 2017-09-20
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Leukemia, Myeloid, AcuteMyeloid DysplasiaOvarian Epithelial Cancer

Genetic Landscape in Women with Metastatic Ovarian Cancer Before and During Treatment with PARP Inhibitors

RECRUITING
NCT06785077Phase NAEuropean Institute of OncologyStarted 2020-10-02
buccal cellsbone marrow cellsperipheral blood cells
Giant Cell ArteritisTemporal ArteritisClonal Hematopoiesis of Indeterminate Potential

Clonal Hematopoiesis in Giant Cell Arteritis

NOT YET RECRUITING
NCT06244069ASST Fatebenefratelli SaccoStarted 2024-03
Temporal arterial biopsyWhole exome sequencingSingle cell transcriptomics
Bone Marrow Failure DisordersVEXAS SyndromeHemoglobinurea, Paroxysmal

Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study

ENROLLING BY INVITATION
NCT07102849National Heart, Lung, and Blood Institute (NHLBI)Started 2025-09-09
Polycythemia Vera

Pegylated Interferon α-2b in Combination With Ruxolitinib for Treating Hydroxyurea-resistant/Intolerant PV

RECRUITING
NCT05870475Phase PHASE2Institute of Hematology & Blood Diseases Hospital, ChinaStarted 2023-06-30
RuxolitinibPegylated interferon α-2b
Myelofibrosis

Clonal Architecture of ASXL1-mutated Myelofibrosis

RECRUITING
NCT05710211Phase NAUniversity Hospital, AngersStarted 2023-04-24
Clonal architecture determination
Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING
NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16
Imatinib withdrawalDasatinibNilotinib
Myeloproliferative Neoplasms

Registry of Patients With MPNs in Taiwan

ACTIVE NOT RECRUITING
NCT03618485Chang Gung Memorial HospitalStarted 2017-04-01

External Resources

Links to major genomics databases and tools