ASB2

Summary

ASB2 (ankyrin repeat and SOCS box containing 2, HGNC:16012) is a protein-coding gene on chromosome 14q32.12, encoding Ankyrin repeat and SOCS box protein 2 (Q96Q27). Substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a member of the ankyrin repeat and SOCS box-containing (ASB) protein family. These proteins play a role in protein degradation by coupling suppressor of cytokine signalling (SOCS) proteins with the elongin BC complex. The encoded protein is a subunit of a multimeric E3 ubiquitin ligase complex that mediates the degradation of actin-binding proteins. This gene plays a role in retinoic acid-induced growth inhibition and differentiation of myeloid leukemia cells. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 51676 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 135 total — 2 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 15 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.24 (unconstrained)
• MANE Select transcript: NM_001202429
• Notable: 135 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16012
Approved symbol	ASB2
Name	ankyrin repeat and SOCS box containing 2
Location	14q32.12
Locus type	gene with protein product
Status	Approved
Aliases	ASB-2
Ensembl gene	ENSG00000100628
Ensembl biotype	protein_coding
OMIM	605759
Entrez	51676

Gene structure

Transcript identifiers

Ensembl transcripts: 66 — 54 protein_coding, 8 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000555019

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 3, TSL 4: 3, TSL 5: 1

ENST00000555019, ENST00000315988, ENST00000553883, ENST00000555287, ENST00000555374, ENST00000555507, ENST00000556062, ENST00000556337, ENST00000556793, ENST00000557613, ENST00000891200, ENST00000891201, ENST00000891202, ENST00000891203, ENST00000891204, ENST00000891205, ENST00000891206, ENST00000891207, ENST00000891208, ENST00000891209, ENST00000891210, ENST00000891211, ENST00000891212, ENST00000968939, ENST00000968940, ENST00000968941, ENST00000968942, ENST00000968943, ENST00000968944, ENST00000968945, ENST00000968946, ENST00000968947, ENST00000968948, ENST00000968949, ENST00000968950, ENST00000968951, ENST00000968952, ENST00000968953, ENST00000968954, ENST00000968955, ENST00000968956, ENST00000968957, ENST00000968958, ENST00000968959, ENST00000968960, ENST00000968961, ENST00000968962, ENST00000968963, ENST00000997957, ENST00000997958, ENST00001027110, ENST00001027111, ENST00001027113, ENST00001027114, ENST00001027116, ENST00001027117, ENST00001027118, ENST00001027119, ENST00001027120, ENST00001027124, ENST00001106596, ENST00001115109, ENST00001115110, ENST00001115111, ENST00001115112, ENST00001134189

RefSeq mRNA: 2 — MANE Select: NM_001202429 NM_001202429, NM_016150

CCDS: CCDS55940, CCDS9915

Canonical transcript exons

ENST00000555019 — 10 exons

Exon	Start	End
ENSE00000659968	93947349	93947520
ENSE00000659969	93950999	93951244
ENSE00000659970	93953352	93953507
ENSE00000659971	93954317	93954483
ENSE00000941237	93939108	93939672
ENSE00002459114	93934166	93934792
ENSE00002521354	93964334	93964612
ENSE00002534964	93976434	93976570
ENSE00003613753	93937698	93937851
ENSE00003689232	93956766	93956870

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 99.15.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6272 / max 341.0309, expressed in 455 samples.

Highest expression (Bgee): skeletal muscle tissue, gastrocnemius, hindlimb stylopod muscle, apex of heart, skeletal muscle organ.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASB2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

20 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	2.1e-16	+0.40	14:93952113:G:C
Artery Aorta	eqtl	1.7e-12	-0.20	14:93994339:T:A
Brain Cerebellar Hemisphere	eqtl	3.6e-09	+0.64	14:93956277:A:T
Artery Tibial	sqtl	5.2e-08	+0.32	14:93952113:G:C
Brain Cerebellum	eqtl	9.1e-08	+0.63	14:93956277:A:T
Artery Aorta	sqtl	6.9e-05	+0.41	14:93951379:C:T
Brain Frontal Cortex BA9	eqtl	1.0e-04	+0.23	14:93976109:C:T
Artery Tibial	eqtl	2.8e-04	-0.16	14:94081551:G:C
Brain Cortex	eqtl	3.8e-04	+0.25	14:93976109:C:T
Breast Mammary Tissue	eqtl	2.4e-03	-0.53	14:93993292:G:A
Testis	eqtl	7.9e-03	+0.26	14:93948511:C:T
Pancreas	eqtl	8.2e-03	-0.37	14:94301243:G:A
Colon Sigmoid	sqtl	1.2e-02	+1.33	14:94521447:T:C
Heart Atrial Appendage	eqtl	1.2e-02	-0.13	14:94066130:C:T
Esophagus Muscularis	eqtl	1.6e-02	+0.31	14:93260437:A:T
Skin Sun Exposed Lower leg	eqtl	1.6e-02	+0.27	14:94602809:G:T
Esophagus Muscularis	sqtl	1.8e-02	+0.25	14:93954650:T:C
Liver	eqtl	2.2e-02	+0.66	14:93102643:A:G
Esophagus Mucosa	eqtl	2.4e-02	-0.11	14:93976109:C:T
Muscle Skeletal	eqtl	3.7e-02	-0.39	14:94129503:T:C

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
144665	1.2697	169
144667	0.8754	195
144653	0.7890	164
144659	0.3455	109
144656	0.0882	57
144654	0.0711	43
144668	0.0616	27
144658	0.0529	17
144655	0.0355	24
144666	0.0213	10

Top tissues by expression

showing 100 of 139 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue	UBERON:0001134	99.15	gold quality
gastrocnemius	UBERON:0001388	99.12	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.11	gold quality
apex of heart	UBERON:0002098	98.06	gold quality
skeletal muscle organ	UBERON:0014892	97.67	gold quality
muscle of leg	UBERON:0001383	97.61	gold quality
muscle tissue	UBERON:0002385	97.29	gold quality
smooth muscle tissue	UBERON:0001135	96.15	gold quality
heart left ventricle	UBERON:0002084	96.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.78	gold quality
right atrium auricular region	UBERON:0006631	95.22	gold quality
left uterine tube	UBERON:0001303	94.78	gold quality
heart	UBERON:0000948	94.68	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.18	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.90	gold quality
lower esophagus	UBERON:0013473	93.84	gold quality
right coronary artery	UBERON:0001625	93.34	gold quality
body of uterus	UBERON:0009853	92.74	gold quality
thoracic aorta	UBERON:0001515	91.82	gold quality
myometrium	UBERON:0001296	91.76	gold quality
ascending aorta	UBERON:0001496	91.74	gold quality
popliteal artery	UBERON:0002250	91.63	gold quality
tibial artery	UBERON:0007610	91.60	gold quality
urinary bladder	UBERON:0001255	91.32	gold quality
descending thoracic aorta	UBERON:0002345	91.28	gold quality
mucosa of stomach	UBERON:0001199	91.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.38	gold quality
colon	UBERON:0001155	89.25	gold quality
fundus of stomach	UBERON:0001160	88.09	gold quality
intestine	UBERON:0000160	87.80	gold quality
left coronary artery	UBERON:0001626	87.79	gold quality
prostate gland	UBERON:0002367	87.35	gold quality
fallopian tube	UBERON:0003889	86.99	gold quality
vermiform appendix	UBERON:0001154	86.50	gold quality
colonic epithelium	UBERON:0000397	85.82	gold quality
gall bladder	UBERON:0002110	84.80	gold quality
transverse colon	UBERON:0001157	84.70	gold quality
small intestine	UBERON:0002108	84.67	gold quality
duodenum	UBERON:0002114	84.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.03	gold quality
esophagus	UBERON:0001043	83.94	gold quality
rectum	UBERON:0001052	83.33	gold quality
lymph node	UBERON:0000029	83.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.96	gold quality
ectocervix	UBERON:0012249	80.59	gold quality
endocervix	UBERON:0000458	79.93	gold quality
stomach	UBERON:0000945	79.84	gold quality
mucosa of transverse colon	UBERON:0004991	78.60	gold quality
lower esophagus mucosa	UBERON:0035834	78.54	gold quality
body of stomach	UBERON:0001161	78.51	gold quality
vagina	UBERON:0000996	78.25	gold quality
uterine cervix	UBERON:0000002	77.07	gold quality
superior frontal gyrus	UBERON:0002661	76.34	gold quality
uterus	UBERON:0000995	76.26	gold quality
right uterine tube	UBERON:0001302	76.10	gold quality
tonsil	UBERON:0002372	75.80	gold quality
spleen	UBERON:0002106	75.55	gold quality
esophagus mucosa	UBERON:0002469	74.77	gold quality
right frontal lobe	UBERON:0002810	74.53	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.18	gold quality
granulocyte	CL:0000094	73.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.74	gold quality
anterior cingulate cortex	UBERON:0009835	73.50	gold quality
material anatomical entity	UBERON:0000465	72.28	gold quality
multicellular organism	UBERON:0000468	72.28	gold quality
anatomical system	UBERON:0000467	72.23	gold quality
frontal cortex	UBERON:0001870	72.13	gold quality
blood	UBERON:0000178	70.81	gold quality
saliva-secreting gland	UBERON:0001044	70.40	gold quality
upper lobe of left lung	UBERON:0008952	69.93	gold quality
minor salivary gland	UBERON:0001830	69.89	gold quality
prefrontal cortex	UBERON:0000451	69.81	gold quality
cerebral cortex	UBERON:0000956	69.59	gold quality
right ovary	UBERON:0002118	69.31	gold quality
subcutaneous adipose tissue	UBERON:0002190	69.21	gold quality
lung	UBERON:0002048	69.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.07	gold quality
leukocyte	CL:0000738	68.57	gold quality
monocyte	CL:0000576	68.00	gold quality
adipose tissue	UBERON:0001013	67.70	gold quality
bone marrow cell	CL:0002092	67.46	silver quality
skin of leg	UBERON:0001511	66.27	gold quality
bone marrow	UBERON:0002371	65.97	gold quality
omental fat pad	UBERON:0010414	65.84	gold quality
thoracic mammary gland	UBERON:0005200	64.98	gold quality
primary visual cortex	UBERON:0002436	64.93	gold quality
zone of skin	UBERON:0000014	64.46	gold quality
ovary	UBERON:0000992	64.20	gold quality
right lung	UBERON:0002167	63.31	gold quality
left ovary	UBERON:0002119	62.39	gold quality
skin of abdomen	UBERON:0001416	62.30	gold quality
right lobe of thyroid gland	UBERON:0001119	61.39	gold quality
metanephros cortex	UBERON:0010533	61.14	gold quality
tibial nerve	UBERON:0001323	61.09	gold quality
thyroid gland	UBERON:0002046	59.83	gold quality
left lobe of thyroid gland	UBERON:0001120	59.30	gold quality
adult mammalian kidney	UBERON:0000082	59.03	gold quality
brain	UBERON:0000955	58.70	gold quality
placenta	UBERON:0001987	58.04	gold quality
right lobe of liver	UBERON:0001114	57.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.25
E-MTAB-4850	no	787.31

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 75 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Skeletal muscle	tissue	489.4
Tongue	tissue	147.3
Cerebral cortex	tissue	10.3
Somatosensory cortex	tissue	10.3
Prefrontal cortex	tissue	9.3
Heart muscle	tissue	9.2
Putamen	tissue	9.2
Motor cortex	tissue	9.1
Occipital cortex	tissue	9.1
Basal ganglia	tissue	9.0
Thalamus	tissue	8.2
Retrosplenial and cingulate cortex	tissue	8.2
Vagina	tissue	8.0
Septum	tissue	8.0
Retrosplenial cortex	tissue	7.6
Temporal cortex	tissue	7.5
Hippocampal formation	tissue	7.3
Entorhinal cortex	tissue	7.3
Ventral forebrain	tissue	7.3
Hypothalamus	tissue	7.0
Lymph node	tissue	6.9
Insular cortex	tissue	6.7
Pons	tissue	6.3
Superior colliculi	tissue	6.1
Midbrain	tissue	5.4
Substantia nigra	tissue	5.4
Appendix	tissue	5.3
Amygdala	tissue	5.0
Periaqueductal gray	tissue	4.6
Spleen	tissue	3.9
Small intestine	tissue	3.9
Esophagus	tissue	3.8
Duodenum	tissue	3.8
Medulla oblongata	tissue	3.7
Corpus callosum	tissue	3.3
Olfactory bulb	tissue	3.3
Caudate putamen	tissue	3.1
Tonsil	tissue	3.0
Spinal cord	tissue	2.9
Stomach 1	tissue	2.3
Cerebellum	tissue	2.2
Postcentral gyrus	tissue	2.2
Frontal cortex	tissue	1.7
Smooth muscle	tissue	1.5
Colon	tissue	1.4
Prostate	tissue	1.3
Salivary gland	tissue	1.2
Urinary bladder	tissue	1.0
Seminal vesicle	tissue	0.9
Adrenal gland	tissue	0.8
Choroid plexus	tissue	0.7
Endometrium 1	tissue	0.6
Lung	tissue	0.5
Adipose tissue	tissue	0.4
Rectum	tissue	0.4
Gallbladder	tissue	0.4
Thymus	tissue	0.4
Bone marrow	tissue	0.4
Epididymis	tissue	0.3
Nucleus accumbens	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 183; highest nTPM — Blood vessel (28.5), Subiculum (5.8), Nucleus of the diagonal band (5.7), Temporo-occipital transitional zone (5.3), Ventral hippocampus (5.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2A, RARA

miRNA regulators (miRDB)

Targeting ASB2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

29 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-549A-5P	96.35	68.08	587
HSA-MIR-6828-3P	96.06	67.61	1155

Functional genomics

gnomAD constraint: pLI 4.42e-19, LOEUF 1.24, missense Z -0.529 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000555019 — one region, missense o/e 1.05.

Literature-anchored findings (GeneRIF, showing 11)

• ASB2 may regulate hematopoietic cell differentiation by modulating cell spreading and actin remodeling through targeting of filamins A and B for degradation. (PMID:18799729)
• By shifting monomeric E3 ligase complexes to dimeric forms through activation of Asb2 transcription, Notch could effectively control the turnover of a variety of substrates and it exerts diverse effects on cell proliferation and differentiation. (PMID:21119685)
• ASB2alpha is a novel regulator of integrin-dependent adhesion of hematopoietic cells (PMID:21737450)
• A model whereby ASB2 contributes to hematopoietic differentiation, in part, through MLL degradation and HOX gene down-regulation. (PMID:22174154)
• These results suggest that ASB2beta but not ASB2alpha might be monoubiquitinated and that the ASB2beta UIM motif, but not its E3 Ub ligase activity, plays a pivotal role in this monoubiquitination. (PMID:22382022)
• Data show that neither endogenous nor exogenously expressed ASB2alpha induces degradation of JAK proteins in hematopoietic cells (PMID:22916308)
• Phosphorylation of serine 323 of ASB2 alpha by Erk kinases is critical for ASB2alpha-mediated degradation of FLNA. (PMID:24044920)
• data therefore reveal ubiquitin acceptor sites in FLNa and establish that ASB2alpha-mediated effects on cell spreading are due to loss of filamins. (PMID:24052262)
• Using ASB2 conditional knockout mice. (PMID:26537633)
• functionally relevant miRNA/mRNA interactions were identified in skeletal muscles of myotonic dystrophy type 1 patients, highlighting the dysfunction of miR-29c and ASB2. (PMID:29955039)
• Notch signaling can initiate Asb2 transcription and NF-kappa B activation in T cell acute lymphoblastic leukemia cells. (PMID:30116272)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	asb2b	ENSDARG00000102490
mus_musculus	Asb2	ENSMUSG00000021200
rattus_norvegicus	Asb2	ENSRNOG00000051619

Paralogs (2): ANKRD24 (ENSG00000089847), UACA (ENSG00000137831)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1929743) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal pericardium morphology	1
abnormal embryo size	1
pale yolk sac	1
abnormal dendritic cell physiology	1
abnormal vitelline vasculature morphology	1
embryonic growth retardation	1
increased T cell number	1
decreased total body fat amount	1
abnormal retina blood vessel morphology	1
preweaning lethality, complete penetrance	1
decreased Ly6C-positive immature NK cell number	1
increased Ly6C-positive immature NK cell number	1
abnormal podosome assembly	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q8HXA6	93.7%	Diamond
Fowlpox virus strain NVSL	Q9J519	30.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CCDC197	protein-coding	256369
FAM181A-AS1	ncRNA	283592
FAM181A	protein-coding	90050
MIR4506	ncRNA	100616140
PRIMA1	protein-coding	145270
DDX24	protein-coding	57062
OTUB2	protein-coding	78990
IFI27L1	protein-coding	122509

Protein

Protein identifiers

Ankyrin repeat and SOCS box protein 2 — Q96Q27 (reviewed: Q96Q27)

All UniProt accessions (5): Q96Q27, G3V2Z2, G3V3P8, G3V484, G3V4B2

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Mediates Notch-induced ubiquitination and degradation of substrates including TCF3/E2A and JAK2. Required during embryonic heart development for complete heart looping. Required for cardiomyocyte differentiation. Specifically promotes the ubiquitination of SMAD9 and targets it for proteasomal degradation, leading to avoid excessive accumulation of SMAD9. Plays a role in the regulation of NK-cell migration by modulating protein levels of filamin A/FLNA via regulation of its ubiquitination and proteasome degradation. Involved in myogenic differentiation and targets filamin FLNB for proteasomal degradation but not filamin FLNA. Also targets DES for proteasomal degradation. Acts as a negative regulator of skeletal muscle mass. Targets filamins FLNA and FLNB for proteasomal degradation. This leads to enhanced adhesion of hematopoietic cells to fibronectin. Required for FLNA degradation in immature cardiomyocytes which is necessary for actin cytoskeleton remodeling, leading to proper organization of myofibrils and function of mature cardiomyocytes. Required for degradation of FLNA and FLNB in immature dendritic cells (DC) which enhances immature DC migration by promoting DC podosome formation and DC-mediated degradation of the extracellular matrix. Does not promote proteasomal degradation of tyrosine-protein kinases JAK1 or JAK2 in hematopoietic cells.

Subunit / interactions. Component of a probable ECS E3 ubiquitin-protein ligase complex which contains CUL5, either RBX1 or RNF7/RBX2, Elongin BC complex (ELOB and ELOC) and ASB2. Interacts with SKP2. Through its interaction with SKP2, likely to bridge the formation of dimeric E3-ubiquitin-protein ligase complexes composed of an ECS complex and an SCF(SKP2) complex. Interacts with JAK2; the interaction targets JAK2 for Notch-mediated proteasomal degradation. Interacts with TCF3/E2A; the interaction is mediated by SKP2 and targets TCF3 for Notch-mediated proteasomal degradation. Interacts with DES.

Subcellular location. Cytoplasm. Cytoskeleton. Stress fiber Cytoplasm. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in muscle cells. Expressed in hematopoietic cells.

Post-translational modifications. Monoubiquitinated. Not monoubiquitinated. Phosphorylation at Ser-371 is required for association with FLNA and subsequent FLNA degradation.

Domain organisation. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin-protein ligase complexes. Both the N-terminus and ANK repeats 1 to 10 are necessary for interaction with filamins. The UIM domain is required for monoubiquitination.

Induction. Induced by all-trans retinoic acid (ATRA). Induced by Notch signaling. Repressed by microRNA miR-29c.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ankyrin SOCS box (ASB) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96Q27-2	1, ASB2beta, muscle-type	yes
Q96Q27-1	2, ASB2alpha, hematopoietic-type

RefSeq proteins (2): NP_001189358, NP_057234 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001496	SOCS_box	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037330	ASB2_SOCS	Domain

Pfam: PF07525, PF12796, PF13606, PF13637

UniProt features (29 total): repeat 12, mutagenesis site 8, domain 2, sequence conflict 2, chain 1, modified residue 1, splice variant 1, sequence variant 1, region of interest 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96Q27-F1	83.96	0.68

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli fibrillar center; cytosol; nucleoplasm

Antibody reliability (HPA): IF approved

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Phosphoserine	371

Mutagenesis-validated functional residues (8)

Position	Phenotype
27–29	abolishes monoubiquitination.
38	abolishes monoubiquitination.
371	abolishes phosphorylation. abolishes degradation of flna. no effect on assembly into ubiquitin-protein ligase complex.
371	phosphomimetic mutant. no effect on isoform 2 flna degradation. no effect on assembly into ubiquitin-protein ligase complex.
596	no interaction with elongin bc complex.
599–600	no interaction with cul5 or rnf7.
600	no interaction with elongin bc complex.
619–622	no interaction with cul5 or rnf7.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-8951664	Neddylation	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-168256	Immune System	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 268 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_DENDRITIC_CELL_MIGRATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_SKELETAL_MUSCLE_ADAPTATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_BARBED_END_ACTIN_FILAMENT_CAPPING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (13): heart looping (GO:0001947), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), skeletal muscle atrophy (GO:0014732), protein ubiquitination (GO:0016567), actin cytoskeleton organization (GO:0030036), intracellular signal transduction (GO:0035556), dendritic cell migration (GO:0036336), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), cardiac muscle cell differentiation (GO:0055007), cardiac muscle cell development (GO:0055013), podosome assembly (GO:0071800), regulation of barbed-end actin filament capping (GO:2000812)

GO Molecular Function (3): cullin family protein binding (GO:0097602), protein binding (GO:0005515), ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), stress fiber (GO:0001725), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), Z disc (GO:0030018)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

42 GO namespaces:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
striated muscle atrophy	1
skeletal muscle adaptation	1
protein modification by small protein conjugation	1
cytoskeleton organization	1
actin filament-based process	1
signal transduction	1
mononuclear cell migration	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
protein-containing complex assembly	1
plasma membrane bounded cell projection assembly	1
regulation of actin filament polymerization	1
regulation of actin filament depolymerization	1
barbed-end actin filament capping	1
protein binding	1
binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
intracellular protein-containing complex	1
transferase complex	1
actomyosin	1
contractile actin filament bundle	1
intracellular membrane-bounded organelle	1
cytoplasm	1
I band	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
cardiac muscle cell differentiation	BP	mutant phenotype
proteasome-mediated ubiquitin-dependent protein catabolic process	BP	mutant phenotype
protein ubiquitination	BP	direct assay
ubiquitin-dependent protein catabolic process	BP	direct assay
ubiquitin ligase complex	CC	direct assay
cullin family protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,068 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASB2	ASB17	Q8WXJ9	852
ASB2	CISH	Q9NSE2	792
ASB2	FTO	Q9C0B1	670
ASB2	JAK3	P52333	666
ASB2	RARA	P10276	656
ASB2	TGM6	O95932	569
ASB2	FLNB	O75369	564
ASB2	ALKBH5	Q6P6C2	550
ASB2	METTL3	Q86U44	534
ASB2	YTHDF2	Q9Y5A9	530
ASB2	FLNA	P21333	523
ASB2	ADAM8	P78325	520
ASB2	METTL14	Q9HCE5	509
ASB2	CUL5	Q93034	487
ASB2	FBXW4	P57775	460

IntAct

Human interaction partners of ASB2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
PRKN	physical association	0.490	2
SMAD9	physical association	0.370	1
NFKB2	association	0.350	1

BioGRID (79 interactions; top human partners by supporting records): CUL5 (Affinity Capture-MS; 7 records), FLNA (Biochemical Activity; 4 records), KMT2A (Affinity Capture-Western; 4 records), TCEB1 (Affinity Capture-Western; 4 records), TCEB2 (Affinity Capture-Western; 4 records), RNF7 (Affinity Capture-Western; 3 records), UBC (Biochemical Activity; 3 records), CUL1 (Affinity Capture-Western; 2 records), DCUN1D3 (Affinity Capture-MS; 2 records), JAK2 (Affinity Capture-Western; 2 records), NFKB2 (Affinity Capture-MS; 2 records), NOX4 (Affinity Capture-Western; 2 records), SKP2 (Affinity Capture-Western; 2 records), SMAD9 (Affinity Capture-Western; 2 records), AGO2 (Affinity Capture-RNA)

SIGNOR signaling

6 signaling interactions:

A	Effect	B	Mechanism
ASB2	“down-regulates quantity by destabilization”	FLNA	polyubiquitination
ASB2	“up-regulates activity”	“Elongin E3-Cul-5”	binding
ASB2	“down-regulates quantity by destabilization”	FLNB	binding
ERK1/2	“up-regulates activity”	ASB2	phosphorylation
MAPK1	“up-regulates activity”	ASB2	phosphorylation
MAPK3	“up-regulates activity”	ASB2	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
Ubiquitin E3 ligase (ASB2, TCEB1, TCEB2, CUL5, RNF7)	5	ELOC, RNF7, ASB2, CUL5, ELOB

Disease & clinical

Genetic variants

Variant evidence for ASB2: 135 ClinVar records (3 pathogenic / likely pathogenic); 11 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	122
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
57811	GRCh38/hg38 14q32.11-32.13(chr14:90255156-95274696)x1	Pathogenic	criteria provided, single submitter	1
1527831	GRCh37/hg19 14q31.3-32.13(chr14:88345625-94773741)x1	Pathogenic	criteria provided, single submitter	1
1348382	NC_000014.8:g.(?93687728)(95560403_?)del	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ASB2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 1,126):

Position(s)	Effect	Δscore	Sites
14:93937696–93937697	donor_loss	1.0000	5
14:93937852–93937853	acceptor_loss	1.0000	5
14:93947347–93947348	donor_loss	1.0000	6
14:93947521–93947522	acceptor_loss	1.0000	6
14:93953524	acceptor_gain	1.0000
14:93954484–93954485	acceptor_loss	1.0000	4
14:93954486	acceptor_gain	1.0000
14:93964579	acceptor_gain	1.0000
14:93934793–93934794	acceptor_loss	0.9900	6
14:93937852	acceptor_loss	0.9900

AlphaMissense

1,551 missense substitutions predicted likely pathogenic (of 4,147 scored), across 402 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D361	8	0.988	0.996
D392	8	0.981	0.993
D255	8	0.979	0.995
F458	8	0.977	0.996
F430	8	0.954	0.994
H95	8	0.952	0.984
H195	8	0.949	0.989
F492	8	0.947	0.995
D514	8	0.945	0.982
F228	8	0.942	0.994
H294	8	0.940	0.988
D449	8	0.929	0.962
H326	8	0.924	0.987
N220	8	0.899	0.997
F369	8	0.894	0.985
D510	8	0.882	0.964
F436	8	0.869	0.974
N266	8	0.840	0.960
H550	8	0.792	0.930
C522	7	0.995	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:605759 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): DICER1-related tumor predisposition (MONDO:0100216)

Orphanet (1): DICER1 tumor-predisposition syndrome (Orphanet:284343)

GWAS associations

11 associations:

Study	Trait	p-value
GCST90002381_507	Eosinophil count	1e-38
GCST90002382_493	Eosinophil percentage of white cells	2e-37
GCST90002382_393	Eosinophil percentage of white cells	4e-27
GCST90002381_508	Eosinophil count	8e-26
GCST004606_173	Eosinophil count	1e-20
GCST004624_40	Sum eosinophil basophil counts	4e-20
GCST004600_72	Eosinophil percentage of white cells	5e-19
GCST004617_82	Eosinophil percentage of granulocytes	9e-17
GCST004623_34	Neutrophil percentage of granulocytes	1e-15
GCST90011899_144	Aspartate aminotransferase levels	4e-10
GCST003030_7	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	5e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects reaction, increases expression, affects methylation, increases methylation	8
Tetrachlorodibenzodioxin	increases expression	4
Air Pollutants	affects expression, increases abundance, increases expression	2
Valproic Acid	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
tungsten carbide	increases expression, affects binding	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	increases expression	1
trimellitic anhydride	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Aldehydes	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Azacitidine	increases expression	1
Bleomycin	decreases expression	1
Cisplatin	increases expression	1
Cobalt	affects binding, increases expression	1
Diuron	decreases expression	1
Doxorubicin	affects expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

3 trials:

NCT	Phase	Status	Title
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03382158	Not specified	RECRUITING	International PPB/DICER1 Registry
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients