ASXL2

Chr 2AD

ASXL transcriptional regulator 2

Also known as: ASXH2, SHAPNS

NCBI Gene: 55252 ENSG00000143970 UniProt: Q76L83 OMIM: 612991

The protein functions as a Polycomb group epigenetic regulator that maintains transcriptional repression of developmental genes and acts as a non-catalytic component of the PR-DUB complex, which deubiquitinates histones and serves as a transcriptional coactivator. Mutations cause Shashi-Pena syndrome, a neurodevelopmental disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.146), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.151 OMIM phenotype

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.

💊

Clinical Trials

1 active or recruiting trial — 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

LoF intolerant — likely haploinsufficient

LoF Constraint

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

1.71Z-score

OE missense 0.82 (0.77–0.88)

609 obs / 739.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.06 (0.03–0.15)

0≤0.351.4

Missense OE0.82 (0.77–0.88)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 3 / 53.2Missense obs/exp: 609 / 739.6Syn Z: -1.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongASXL2-related developmental delay, macrocephaly, and dysmorphic featuresLOFAD

0.2599th %ile

GOF

0.2198th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.15

DN1 literature citation

Literature Evidence

DNWe were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neuroPMID:27693232

LOFHere we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor.PMID:28516957

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