ASXL2

Summary

ASXL2 (ASXL transcriptional regulator 2, HGNC:23805) is a protein-coding gene on chromosome 2p23.3, encoding Putative Polycomb group protein ASXL2 (Q76L83). Putative Polycomb group (PcG) protein.

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.

Source: NCBI Gene 55252 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 676 total — 13 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 46
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23805
Approved symbol	ASXL2
Name	ASXL transcriptional regulator 2
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	ASXH2, FLJ10898, KIAA1685
Ensembl gene	ENSG00000143970
Ensembl biotype	protein_coding
OMIM	612991
Entrez	55252

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000336112, ENST00000404843, ENST00000435504, ENST00000497092, ENST00000672666, ENST00000673455, ENST00000682588

RefSeq mRNA: 3 — MANE Select: NM_018263 NM_001369346, NM_001369347, NM_018263

CCDS: CCDS92720

Canonical transcript exons

ENST00000435504 — 13 exons

Exon	Start	End
ENSE00000962989	25753534	25753639
ENSE00000962990	25749696	25750413
ENSE00001332882	25756018	25756114
ENSE00001627569	25878166	25878487
ENSE00001683179	25733753	25744476
ENSE00002283549	25835538	25835540
ENSE00003569708	25806229	25806337
ENSE00003575266	25845481	25845563
ENSE00003583305	25771440	25771540
ENSE00003588471	25759482	25759645
ENSE00003605878	25767583	25767726
ENSE00003626386	25768742	25768868
ENSE00003651028	25799385	25799535

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.6462 / max 207.6385, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27399	19.6644	1802
27398	1.5178	657
27400	0.7268	414
27395	0.4787	80
27401	0.2585	110

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	98.47	gold quality
corpus epididymis	UBERON:0004359	98.17	gold quality
cauda epididymis	UBERON:0004360	98.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.73	gold quality
trabecular bone tissue	UBERON:0002483	97.69	gold quality
upper leg skin	UBERON:0004262	96.97	gold quality
lower lobe of lung	UBERON:0008949	96.74	gold quality
bronchial epithelial cell	CL:0002328	96.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.16	gold quality
epithelium of bronchus	UBERON:0002031	96.12	gold quality
bronchus	UBERON:0002185	96.07	gold quality
superficial temporal artery	UBERON:0001614	95.50	gold quality
biceps brachii	UBERON:0001507	95.33	gold quality
skin of hip	UBERON:0001554	95.10	gold quality
epithelium of nasopharynx	UBERON:0001951	94.94	gold quality
mammalian vulva	UBERON:0000997	94.78	gold quality
superior surface of tongue	UBERON:0007371	94.41	gold quality
oral cavity	UBERON:0000167	94.20	gold quality
mammary duct	UBERON:0001765	94.04	gold quality
trachea	UBERON:0003126	93.57	gold quality
diaphragm	UBERON:0001103	93.56	gold quality
thymus	UBERON:0002370	93.39	gold quality
jejunal mucosa	UBERON:0000399	93.31	gold quality
adult organism	UBERON:0007023	93.26	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.23	gold quality
hair follicle	UBERON:0002073	93.22	gold quality
mucosa of urinary bladder	UBERON:0001259	92.99	gold quality
tongue squamous epithelium	UBERON:0006919	92.91	gold quality
tongue	UBERON:0001723	92.83	gold quality
pharyngeal mucosa	UBERON:0000355	92.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.11
E-GEOD-99795	no	90.66

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
TET2	Activation

Upstream regulators (CollecTRI, top): KMT2A, TFAP2A

miRNA regulators (miRDB)

198 targeting ASXL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• the apparent occurrence of an unusual TG 3’ splice site in intron 2 is discussed (PMID:17672918)
• ASXL1 represses, whereas ASXL2 increases, the expression of adipogenic genes, most of which are PPARgamma targets (PMID:21047783)
• identify a high-frequency mutation in t(8;21)/RUNX1-RUNX1T1 acute myekoid leukemia (AML) and identify the need for future studies to investigate the clinical and biological relevance of ASXL2 mutations in this unique subset of AML (PMID:24973361)
• WTIP interacts with ASXL2 and blocks ASXL2-mediated activation of retinoic acid signaling. (PMID:25065743)
• ASXL1, ASXL2 and ASXL3 are epigenetic scaffold proteins that are involved in the pathogenesis of non-cancerous diseases and cancers.[Review] (PMID:25835095)
• inactivation of the BAP1/ASXL2 axis might contribute to cancer development. (PMID:26416890)
• Data indicate higher ASXL2 expression in ERalpha-positive patients, suggesting that ASXL2 could be a prognostic marker in breast cancer. (PMID:26640146)
• de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype; this report expands the germline disorders that are linked to the ASXL genes (PMID:27693232)
• Mutation in ASXL2 is associated with core-binding factor acute myeloid leukemia. (PMID:27798625)
• ASXL2 mutation is associated with acute myeloid leukemia. (PMID:28063196)
• after KIT and NRAS, ASXL2 is among the most frequently mutated genes in t(8;21)-positive acute myeloid leukemia (AML), occurring in almost 17% of the patients in the cohort; high incidence and the exclusivity of ASXL2 mutation in this AML subset implies its particular role as a potential co-operating event in leukemogenesis of t(8;21)-positive AML (PMID:28090090)
• ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. (PMID:28516957)
• Loss of ASXL2 expression is associated with tumorigenesis. (PMID:29284740)
• Infrequent occurrence of TET1, TET3, and ASXL2 mutations in myelodysplastic/myeloproliferative neoplasms (PMID:29531217)
• ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex. (PMID:30251205)
• ASXL2 mutation was frequent in non-de novo AML1-ETO-negative AML. 6 ASXL2 mutated AML patients were studied in detail and all ASXL2-mutated de-novo AML was positive for AML1-ETO; however, other ASXL2-mutated AML belonged to non-de-novo AML and they all were negative for AML1-ETO in this study. (PMID:31637484)
• ASXL2 gene mutation may not be closely related with C-KIT gene mutation (PMID:32027264)
• Association between serum antiASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension. (PMID:32945427)
• Kinetic Characterization of ASXL1/2-Mediated Allosteric Regulation of the BAP1 Deubiquitinase. (PMID:33731362)
• Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature. (PMID:33751773)
• [The Relationship between ASXL2 and ZBTB7A Gene Mutations and Prognosis in Patients with Acute Myeloid Leukemia]. (PMID:33812414)
• Exploring the landscape of somatic ASXL2 mutations in myeloid neoplasms: Frequency and clinical implications. (PMID:38613831)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	asxl2	ENSDARG00000076501
mus_musculus	Asxl2	ENSMUSG00000037486
rattus_norvegicus	Asxl2	ENSRNOG00000011908
drosophila_melanogaster	Asx	FBGN0261823

Paralogs (2): ASXL3 (ENSG00000141431), ASXL1 (ENSG00000171456)

Protein

Protein identifiers

Putative Polycomb group protein ASXL2 — Q76L83 (reviewed: Q76L83)

Alternative names: Additional sex combs-like protein 2

All UniProt accessions (5): Q76L83, A0A5F9ZH08, A0A5F9ZHC8, A0A5F9ZHN2, E7EWD6

UniProt curated annotations — full annotation on UniProt →

Function. Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility. Involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator for PPARG and enhances its adipocyte differentiation-inducing activity; the function seems to involve differential recruitment of acetylated and methylated histone H3. Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-119’ (H2AK119ub1). 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. ASXL1, ASXL2 and ASXL3 function redundantly in the PR-DUB complex. The ASXL proteins are essential for chromatin recruitment and transcriptional activation of associated genes. ASXL1 and ASXL2 are important for BAP1 protein stability.

Subunit / interactions. Core component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3, and one of MBD5 or MBD6. Distinct combinations of ASXL and MBD proteins may preferentially bind specific histone modification marks. The PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1 and OGT; KDM1B specifically associates with ASXL2 PR-DUB complexes. Interacts (via PHD domain) with MBD5 and MBD6 (via MBD domain); the interaction is probably direct and mediates association of MBD proteins with the PR-DUB core. Interacts with PPARA and PPARG.

Subcellular location. Nucleus.

Disease relevance. Shashi-Pena syndrome (SHAPNS) [MIM:617190] An autosomal dominant syndrome characterized by delayed psychomotor development, intellectual disability of variable severity, macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, and hypotonia. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving ASXL2 is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with KAT6A generates a KAT6A-ASXL2 fusion protein.

Domain organisation. Contains two Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which may be required for an association with nuclear receptors.

Similarity. Belongs to the Asx family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q76L83-1	1	yes
Q76L83-2	2

RefSeq proteins (3): NP_001356275, NP_001356276, NP_060733* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007759	Asxl_HARE-HTH	Domain
IPR024811	ASX/ASX-like	Family
IPR026905	ASX-like_PHD	Domain
IPR028020	ASX_DEUBAD_dom	Domain
IPR044867	DEUBAD_dom	Domain

Pfam: PF05066, PF13919, PF13922

UniProt features (54 total): compositionally biased region 18, region of interest 10, modified residue 9, sequence variant 4, short sequence motif 3, sequence conflict 3, domain 2, splice variant 2, chain 1, zinc finger region 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9ATN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q76L83-F1	47.17	0.04

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 20–21 (breakpoint for translocation to form kat6a-asxl2 protein)

Post-translational modifications (9): 146, 524, 562, 571, 600, 637, 641, 648, 1319

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 330 (showing top): GCACCTT_MIR18A_MIR18B, E2F_Q4, AGGAAGC_MIR5163P, E2F_Q4_01, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, MODULE_255, TGCACTT_MIR519C_MIR519B_MIR519A, CMYB_01, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, MODULE_317, TGACCTY_ERR1_Q2, SRF_Q5_01, MAYBURD_RESPONSE_TO_L663536_UP

GO Biological Process (5): animal organ morphogenesis (GO:0009887), positive regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035360), positive regulation of fat cell differentiation (GO:0045600), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): DNA binding (GO:0003677), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), peroxisome proliferator activated receptor binding (GO:0042975), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), PR-DUB complex (GO:0035517), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
anatomical structure morphogenesis	1
animal organ development	1
peroxisome proliferator activated receptor signaling pathway	1
regulation of peroxisome proliferator activated receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nucleic acid binding	1
transition metal ion binding	1
signaling receptor binding	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
PcG protein complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

4028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASXL2	BRPF1	P55201	990
ASXL2	KAT6B	Q8WYB5	982
ASXL2	ING5	Q8WYH8	982
ASXL2	MEAF6	Q9HAF1	929
ASXL2	RUNX1	Q01196	919
ASXL2	ZNF462	Q96JM2	914
ASXL2	NCOA2	Q15596	911
ASXL2	H3-3A	P06351	891
ASXL2	H3C1	P02295	891
ASXL2	H3-4	Q16695	891
ASXL2	H3-7	Q5TEC6	891
ASXL2	H3-5	Q6NXT2	891
ASXL2	H3C14	Q71DI3	891
ASXL2	ING4	Q9UNL4	864
ASXL2	BRD1	O95696	843

IntAct

45 interactions, top by confidence:

A	B	Type	Score
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
SPOP	JUN	psi-mi:“MI:0914”(association)	0.600
ASXL2	SPOP	psi-mi:“MI:0915”(physical association)	0.600
SPOP	ASXL2	psi-mi:“MI:2364”(proximity)	0.600
ASXL2	SPOP	psi-mi:“MI:2364”(proximity)	0.600
SPOP	ASXL2	psi-mi:“MI:0915”(physical association)	0.600
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
ABLIM2	AFDN	psi-mi:“MI:0914”(association)	0.530
BAP1	HAT1	psi-mi:“MI:0914”(association)	0.530
EN1	NFIB	psi-mi:“MI:2364”(proximity)	0.470
Bap1	HCFC1	psi-mi:“MI:0915”(physical association)	0.400
ASXL2	PRPF40A	psi-mi:“MI:0915”(physical association)	0.370
FOXK2	PHF20L1	psi-mi:“MI:0914”(association)	0.350
BAP1	IPO5	psi-mi:“MI:0914”(association)	0.350
ASXL2	CTRL	psi-mi:“MI:0914”(association)	0.350
DAB2IP	DDX3Y	psi-mi:“MI:0914”(association)	0.350
ASXL2	OGT	psi-mi:“MI:0914”(association)	0.350
BAP1	PSMD11	psi-mi:“MI:0914”(association)	0.350
ELF1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
ELF2	SETD1A	psi-mi:“MI:2364”(proximity)	0.270
ELF4	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
ERG	BCL9	psi-mi:“MI:2364”(proximity)	0.270
FEV	TAF4	psi-mi:“MI:2364”(proximity)	0.270
FOXI1	BCL9	psi-mi:“MI:2364”(proximity)	0.270
GATA2	BCL9	psi-mi:“MI:2364”(proximity)	0.270
HNF1B	BCL9	psi-mi:“MI:2364”(proximity)	0.270
HNF4A	TAF4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (344): KDM1B (Affinity Capture-MS), MBD6 (Affinity Capture-MS), BAP1 (Affinity Capture-MS), FOXK1 (Affinity Capture-MS), MBD5 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-MS), ASXL2 (Affinity Capture-Western), BAP1 (Affinity Capture-Western), ASXL2 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4IYX6, A0A1L8H0H2, A5X7A0, A7XYJ6, E1BE02, F6NSX9, F8VPJ6, O35914, O57415, P37275, P59598, P59759, Q03172, Q13029, Q2KHR2, Q3UH06, Q5EXX3, Q5R7F2, Q5ZIE8, Q5ZLR2, Q62947, Q63755, Q64318, Q6NRM0, Q6ZPY7, Q76L83, Q7LBC6, Q7YR76, Q80VX4, Q86V15, Q8BHZ4, Q8BLG0, Q8BRH4, Q8BX22, Q8BZ32, Q8C0C0, Q8IZQ8, Q8NEZ4, Q8R5I7, Q8VIM5

Diamond homologs: P59598, Q5ZM88, Q76L83, Q8BZ32, Q8C4A5, Q8IXJ9, Q9C0F0, Q9V727

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ASXL2	“up-regulates activity”	PPARG	binding
ASXL2	“up-regulates quantity by expression”	TET2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
UCH proteinases	6	20.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	34.9×	3e-06
transcription by RNA polymerase II	6	8.5×	4e-03
positive regulation of gene expression	9	7.0×	5e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — AML, BLCA.

Clinical variants and AI predictions

ClinVar

676 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	15
Uncertain significance	346
Likely benign	179
Benign	47

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1321869	NM_018263.6(ASXL2):c.2485C>T (p.Gln829Ter)	Pathogenic
268122	NM_018263.6(ASXL2):c.2424del (p.Thr809fs)	Pathogenic
268123	NM_018263.6(ASXL2):c.2081dup (p.Gly696fs)	Pathogenic
268124	NM_018263.6(ASXL2):c.1225_1228del (p.Pro409fs)	Pathogenic
268125	NM_018263.6(ASXL2):c.2472del (p.Ser825fs)	Pathogenic
268126	NM_018263.6(ASXL2):c.2971_2974del (p.Gly991fs)	Pathogenic
268127	NM_018263.6(ASXL2):c.1288G>T (p.Glu430Ter)	Pathogenic
3377014	NM_018263.6(ASXL2):c.1840C>T (p.Arg614Ter)	Pathogenic
3958209	NM_018263.6(ASXL2):c.2837_2841del (p.Ile946fs)	Pathogenic
4527015	NM_018263.6(ASXL2):c.3658_3659del (p.Leu1220fs)	Pathogenic
523922	NM_018263.6(ASXL2):c.2606del (p.Pro868_Ser869insTer)	Pathogenic
666552	NM_018263.6(ASXL2):c.1228A>T (p.Lys410Ter)	Pathogenic
666592	NM_018263.6(ASXL2):c.1242_1243del (p.Ser415fs)	Pathogenic
1338778	NM_018263.6(ASXL2):c.3424del (p.His1142fs)	Likely pathogenic
1992351	NM_018263.6(ASXL2):c.1143-1G>T	Likely pathogenic
2429973	NM_018263.6(ASXL2):c.2326A>C (p.Thr776Pro)	Likely pathogenic
2431484	NM_018263.6(ASXL2):c.2707C>T (p.Gln903Ter)	Likely pathogenic
2577974	NM_018263.6(ASXL2):c.3143del (p.Ser1048fs)	Likely pathogenic
3242174	NM_018263.6(ASXL2):c.1207A>T (p.Lys403Ter)	Likely pathogenic
3366969	NM_018263.6(ASXL2):c.1471C>T (p.Gln491Ter)	Likely pathogenic
3776086	NM_018263.6(ASXL2):c.2729dup (p.Ala911fs)	Likely pathogenic
3905849	NM_018263.6(ASXL2):c.2762dup (p.Ala922fs)	Likely pathogenic
4085835	NM_018263.6(ASXL2):c.1253del (p.Ser418fs)	Likely pathogenic
4292491	NM_018263.6(ASXL2):c.2641del (p.Ala881fs)	Likely pathogenic
4293380	NM_018263.6(ASXL2):c.2693del (p.Lys898fs)	Likely pathogenic
449235	NM_018263.6(ASXL2):c.4228T>G (p.Cys1410Gly)	Likely pathogenic
4526446	NM_018263.6(ASXL2):c.1255_1256del (p.Leu419fs)	Likely pathogenic
987075	NM_018263.6(ASXL2):c.1309C>T (p.Gln437Ter)	Likely pathogenic

SpliceAI

3618 predictions. Top by Δscore:

Variant	Effect	Δscore
2:25736500:T:TA	donor_gain	1.0000
2:25750409:CAGAA:C	acceptor_gain	1.0000
2:25750411:GAA:G	acceptor_gain	1.0000
2:25750414:C:CC	acceptor_gain	1.0000
2:25753568:T:A	donor_gain	1.0000
2:25759477:CGCA:C	donor_loss	1.0000
2:25759641:TTGTC:T	acceptor_gain	1.0000
2:25759642:TGTC:T	acceptor_gain	1.0000
2:25759643:GTC:G	acceptor_gain	1.0000
2:25759643:GTCC:G	acceptor_loss	1.0000
2:25759644:TC:T	acceptor_gain	1.0000
2:25759644:TCCTA:T	acceptor_loss	1.0000
2:25759645:CC:C	acceptor_gain	1.0000
2:25759646:C:CC	acceptor_gain	1.0000
2:25759647:T:G	acceptor_loss	1.0000
2:25759649:C:CT	acceptor_gain	1.0000
2:25767581:A:AC	donor_gain	1.0000
2:25767582:C:CT	donor_gain	1.0000
2:25767727:C:CC	acceptor_gain	1.0000
2:25768713:T:TA	donor_gain	1.0000
2:25768736:GCCTA:G	donor_loss	1.0000
2:25768737:CCTA:C	donor_loss	1.0000
2:25768738:CTACC:C	donor_loss	1.0000
2:25768739:TA:T	donor_loss	1.0000
2:25768740:A:T	donor_loss	1.0000
2:25768741:C:G	donor_loss	1.0000
2:25768864:AGCGC:A	acceptor_gain	1.0000
2:25768865:GCGC:G	acceptor_gain	1.0000
2:25768866:CGC:C	acceptor_gain	1.0000
2:25768866:CGCC:C	acceptor_gain	1.0000

AlphaMissense

9340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:25742044:G:C	C1431W	1.000
2:25742045:C:T	C1431Y	1.000
2:25742046:A:G	C1431R	1.000
2:25742053:G:C	C1428W	1.000
2:25742054:C:T	C1428Y	1.000
2:25742055:A:G	C1428R	1.000
2:25742074:G:C	C1421W	1.000
2:25742076:A:G	C1421R	1.000
2:25742086:G:C	C1417W	1.000
2:25742087:C:T	C1417Y	1.000
2:25742088:A:G	C1417R	1.000
2:25742089:G:C	F1416L	1.000
2:25742089:G:T	F1416L	1.000
2:25742091:A:G	F1416L	1.000
2:25742099:C:T	C1413Y	1.000
2:25742100:A:G	C1413R	1.000
2:25742107:G:C	C1410W	1.000
2:25742108:C:G	C1410S	1.000
2:25742108:C:T	C1410Y	1.000
2:25742109:A:G	C1410R	1.000
2:25742109:A:T	C1410S	1.000
2:25742131:G:C	C1402W	1.000
2:25742133:A:G	C1402R	1.000
2:25756026:A:G	L343P	1.000
2:25756037:C:A	W339C	1.000
2:25756037:C:G	W339C	1.000
2:25756039:A:G	W339R	1.000
2:25756039:A:T	W339R	1.000
2:25756061:G:C	F331L	1.000
2:25756061:G:T	F331L	1.000

dbSNP variants (sampled 300 via entrez): RS1000011826 (2:25807928 A>G), RS1000028604 (2:25766606 A>C), RS1000046824 (2:25869102 T>A,C,G), RS1000048715 (2:25811908 C>T), RS1000050791 (2:25862072 G>A), RS1000057953 (2:25757522 A>C,T), RS1000110689 (2:25801558 T>C), RS1000127502 (2:25863458 C>G,T), RS1000138178 (2:25772965 T>C), RS1000139273 (2:25783561 CT>C,CTT,CTTTTTT), RS1000174245 (2:25738917 C>T), RS1000181632 (2:25816257 A>G), RS1000189576 (2:25862984 A>T), RS1000208211 (2:25779181 C>T), RS1000227482 (2:25867831 G>A)

Disease associations

OMIM: gene MIM:612991 | disease phenotypes: MIM:617190

GenCC curated gene-disease

Disease	Classification	Inheritance
Shashi-Pena syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (6): Shashi-Pena syndrome (MONDO:0014963), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), vascular disorder (MONDO:0005385), syndromic intellectual disability (MONDO:0000508)

Orphanet (4): Shashi-Pena syndrome (Orphanet:689408), Rare genetic syndromic intellectual disability (Orphanet:183763), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000396	Overfolded helix
HP:0000455	Broad nasal tip
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000527	Long eyelashes
HP:0000664	Synophrys
HP:0000750	Delayed speech and language development
HP:0000939	Osteoporosis
HP:0000998	Hypertrichosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001511	Intrauterine growth retardation
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001943	Hypoglycemia
HP:0002057	Prominent glabella
HP:0002119	Ventriculomegaly

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST002921_3	Multiple myeloma	3.000000e-06
GCST002922_3	Multiple myeloma and monoclonal gammopathy	5.000000e-06
GCST006979_913	Heel bone mineral density	6.000000e-13
GCST006979_914	Heel bone mineral density	6.000000e-10
GCST009560_6	Decreased low contrast letter acuity in multiple sclerosis	3.000000e-06
GCST010083_287	Hemoglobin levels	7.000000e-13
GCST010244_354	Triglyceride levels	4.000000e-08
GCST010653_56	Thyroid stimulating hormone levels	4.000000e-12
GCST012249_1	IgG bisecting N-acetyl glucosamine phenotypes (multivariate analysis)	6.000000e-10
GCST90000025_802	Appendicular lean mass	1.000000e-22
GCST90002385_121	High light scatter reticulocyte count	8.000000e-30
GCST90002386_240	High light scatter reticulocyte percentage of red cells	1.000000e-29
GCST90002387_253	Immature fraction of reticulocytes	1.000000e-15
GCST90002404_12	Red cell distribution width	7.000000e-13
GCST90002405_116	Reticulocyte count	2.000000e-26
GCST90002406_11	Reticulocyte fraction of red cells	4.000000e-27

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008385	visual acuity measurement
EFO:0004509	hemoglobin measurement
EFO:0004530	triglyceride measurement
EFO:0008426	IgG bisecting N-acetyl glucosamine measurement
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D014652	Vascular Diseases	C14.907

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	decreases methylation	1
1-hydroxypyrene	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SD75	HAP1 ASXL2 (-) 1	Cancer cell line	Male
CVCL_SD76	HAP1 ASXL2 (-) 2	Cancer cell line	Male
CVCL_SD77	HAP1 ASXL2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)