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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— ASXL2

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 342 VUS of 673 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ASXL2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.06 (0.03–0.15)

0≤0.351.4

Missense OE?0.82 (0.77–0.88)

0≤0.61.4

Synonymous OE?1.11

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

This gene — mechanism propensity

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 · 93% of P/LP variants are LoF · 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 neuro1

LOFHere we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor.2

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

673 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic15

VUS342

Likely Benign201

Benign47

Conflicting42

Pathogenic

Likely Pathogenic

342

VUS

201

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	0	0	0	13
Likely Pathogenic	13	2	0	0	15
VUS	9	323	6	4	342
Likely Benign	1	49	33	118	201
Benign	0	23	14	10	47
Conflicting	—				42
Total	36	397	53	132	660

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap ASXL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →