ASXL1

Chr 20AD

ASXL transcriptional regulator 1

Also known as: BOPS, MDS

NCBI Gene: 171023 ENSG00000171456 UniProt: Q8IXJ9 OMIM: 612990

The protein functions as a chromatin-binding Polycomb group member that disrupts chromatin to enhance transcription of certain genes while repressing others, and acts as a ligand-dependent co-activator for retinoic acid receptor. Mutations cause Bohring-Opitz syndrome and myelodysplastic syndrome through an autosomal dominant inheritance pattern. The pathogenic mechanism involves disrupted chromatin regulation affecting gene transcription patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is similar to the Drosophila additional sex combs gene, which encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by this gene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.792 OMIM phenotypes

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.

💊

Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.77

OE 0.59 (0.44–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.64Z-score

OE missense 0.94 (0.88–0.99)

791 obs / 842.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.44–0.79)

0≤0.351.4

Missense OE?0.94 (0.88–0.99)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 31 / 52.7Missense obs/exp: 791 / 842.9Syn Z: -0.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveASXL1-related Bohring-Opitz syndromeLOFAD

This gene — mechanism propensity

0.5575th %ile

GOF

0.4382th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFAdditional sex combs-like 1 (ASXL1) is frequently mutated in a variety of myeloid malignancies, resulting in expression of a C-terminal-truncated ASXL1 protein that confers gain of function on the ASXL1-BAP1 deubiquitinase (DUB) complex.1

LOFDe novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome2

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

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

Diffuse Large B Cell Lymphoma

Characterization and Clinical Impact of the Gut Microbiota in Lymphoma

RECRUITING

NCT06161896Lars Møller PedersenStarted 2024-05-06

Stool samples

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

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

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

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