ASXL2

Chr 2AD

ASXL transcriptional regulator 2

Also known as: ASXH2, SHAPNS

NCBI Gene: 55252ENSG00000143970UniProt: Q76L83

This gene encodes a member of a family of epigenetic regulators that bind various histone-modifying enzymes and are involved in the assembly of transcription factors at specific genomic loci. Naturally occurring mutations in this gene are associated with cancer in several tissue types (breast, bladder, pancreas, ovary, prostate, and blood). This gene plays an important role in neurodevelopment, cardiac function, adipogenesis, and osteoclastogenesis. [provided by RefSeq, Feb 2017]

Primary Disease Associations & Inheritance

Shashi-Pena syndromeMIM #617190
AD
582
ClinVar variants
41
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— ASXL2
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
41 Pathogenic / Likely Pathogenic· 280 VUS of 582 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.15LOEUF
pLI 1.000
Z-score 6.37
OE 0.06 (0.03–0.15)
Highly constrained

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

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.
1.71Z-score
OE missense 0.82 (0.77–0.88)
609 obs / 739.6 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.0.06 (0.03–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.77–0.88)
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.1.11
0≤1.21.6
LoF obs/exp: 3 / 53.2Missense obs/exp: 609 / 739.6Syn Z: -1.40

ClinVar Variant Classifications

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic13
VUS280
Likely Benign181
Benign47
Conflicting33
28
Pathogenic
13
Likely Pathogenic
280
VUS
181
Likely Benign
47
Benign
33
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
20
0
28
Likely Pathogenic
8
1
4
0
13
VUS
6
249
21
4
280
Likely Benign
1
41
33
106
181
Benign
0
20
16
11
47
Conflicting
—33
Total2331194121582

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

View in ClinVar →

Protein Context — Lollipop Plot

ASXL2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ASXL2-related developmental delay, macrocephaly, and dysmorphic features

strong
ADLoss 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

Shashi-Pena syndrome

MIM #617190

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — ASXL2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations.
Micol JB et al.·Blood
2014Clinical trial
De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.
Shashi V et al.·Am J Hum Genet
2016
Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study.
Kawashima N et al.·Ann Hematol
2019Clinical trial
[Frequency and clinical features of ASXL2 gene mutation in acute myeloid leukemia patients with AML1- ETO fusion gene positive].
Zhao JX et al.·Zhonghua Xue Ye Xue Za Zhi
2016Cohort
A de novo and novel nonsense variants in ASXL2 gene is associated with Shashi-Pena syndrome.
Jiao Z et al.·Eur J Med Genet
2022Case report
Identification of a de novo variant in the ASXL2 gene related to Shashi-Pena syndrome.
Zheng Y et al.·Mol Genet Genomic Med
2023Case report
[Relation of ASXL2 Gene Mutation with Clinical Characteristics, Prognosis and C-KIT Gene Mutation in AML Patients with AML1- ETO Fusion Gene].
Cui P et al.·Zhongguo Shi Yan Xue Ye Xue Za Zhi
2020Cohort
ASXL2 Modulates Chromatin Remodeling to Direct Osteogenesis and Multiple Cell Fate in hPDLSCs.
Yang T et al.·Int Dent J
2025Functional
ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis.
Yamato G et al.·Genes Chromosomes Cancer
2017Cohort
Genetic Variants Associated with Suspected Neonatal Hypoxic Ischaemic Encephalopathy: A Study in a South African Context.
Foden CJ et al.·Int J Mol Sci
2025
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
Bohring-Opitz SyndromeASXL1 Gene MutationShashi-Pena Syndrome

ASXL-Related Disorders Natural History Study

RECRUITING
NCT03303716University of California, Los AngelesStarted 2017-09-20

External Resources

Links to major genomics databases and tools