SH2B3

Summary

SH2B3 (SH2B adaptor protein 3, HGNC:29605) is a protein-coding gene on chromosome 12q24.12, encoding SH2B adapter protein 3 (Q9UQQ2). Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.

This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10019 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SH2B3-related immune system disorder (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 216
• Clinical variants (ClinVar): 1,035 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 51
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_005475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29605
Approved symbol	SH2B3
Name	SH2B adaptor protein 3
Location	12q24.12
Locus type	gene with protein product
Status	Approved
Aliases	LNK, IDDM20
Ensembl gene	ENSG00000111252
Ensembl biotype	protein_coding
OMIM	605093
Entrez	10019

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000341259, ENST00000538307, ENST00000550925, ENST00000896496, ENST00000896497, ENST00000935781, ENST00000935782, ENST00000935783

RefSeq mRNA: 2 — MANE Select: NM_005475 NM_001291424, NM_005475

CCDS: CCDS76602, CCDS9153

Canonical transcript exons

ENST00000341259 — 8 exons

Exon	Start	End
ENSE00000755156	111446753	111446854
ENSE00000755157	111446942	111447033
ENSE00000755159	111447330	111447544
ENSE00000755160	111447656	111447827
ENSE00000834836	111447125	111447219
ENSE00001335860	111447983	111451623
ENSE00001356969	111405923	111406277
ENSE00001378402	111418119	111418877

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 94.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4997 / max 265.7182, expressed in 1772 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128037	12.5773	1751
128039	2.7726	1144
128038	1.1136	416
128041	0.0362	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.81	gold quality
mononuclear cell	CL:0000842	94.80	gold quality
leukocyte	CL:0000738	94.70	gold quality
granulocyte	CL:0000094	93.05	gold quality
heart right ventricle	UBERON:0002080	89.85	gold quality
left ventricle myocardium	UBERON:0006566	89.45	gold quality
spleen	UBERON:0002106	89.14	gold quality
secondary oocyte	CL:0000655	88.99	gold quality
blood	UBERON:0000178	88.73	gold quality
lower lobe of lung	UBERON:0008949	88.72	gold quality
apex of heart	UBERON:0002098	88.44	gold quality
oocyte	CL:0000023	88.39	gold quality
adrenal tissue	UBERON:0018303	88.35	gold quality
heart left ventricle	UBERON:0002084	87.81	gold quality
cardiac ventricle	UBERON:0002082	87.69	gold quality
vermiform appendix	UBERON:0001154	87.37	gold quality
bone marrow cell	CL:0002092	87.24	gold quality
gall bladder	UBERON:0002110	86.95	gold quality
visceral pleura	UBERON:0002401	86.72	gold quality
myocardium	UBERON:0002349	86.50	gold quality
decidua	UBERON:0002450	86.46	gold quality
lung	UBERON:0002048	86.21	gold quality
upper lobe of lung	UBERON:0008948	86.03	gold quality
upper lobe of left lung	UBERON:0008952	85.87	gold quality
omental fat pad	UBERON:0010414	85.78	gold quality
peritoneum	UBERON:0002358	85.72	gold quality
stromal cell of endometrium	CL:0002255	85.65	gold quality
right lung	UBERON:0002167	85.54	gold quality
bone marrow	UBERON:0002371	85.51	gold quality
lymph node	UBERON:0000029	85.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.85
E-GEOD-110499	no	537.26

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BCL2L1	Repression

miRNA regulators (miRDB)

203 targeting SH2B3, 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-4533	100.00	69.48	2758
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-1252-5P	100.00	69.80	2774
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 40)

• Adaptor Lnk is a negative regulator in the TNFalpha-signaling pathway mediating ERK inhibition suggesta a role for Lnk in the interplay between PI3K and ERK triggered by TNFalpha in vascular endothelial cells. (PMID:16644735)
• TNF-alpha induces Lnk expression through PI3K-dependent signaling pathway in umbilical vein endothelial cells (PMID:17007883)
• Data show that Lnk bound directly to c-Kit through Tyr(568) on juxtamembrane domain of c-Kit. (PMID:18588518)
• A nonsynonymous SNP at 12q24, in SH2B3, associated significantly with myocardial infarction in six different populations. (PMID:19198610)
• Lnk is a potent inhibitor of JAK2V617F constitutive activity. (PMID:19293402)
• in parallel to binding wild-type JAK2 and c-KIT, Lnk associates with and is phosphorylated by mutant alleles of JAK2 and c-KIT. (PMID:19375649)
• myeloproliferative neoplasms patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34(+) early progenitors were abnormally abundant (PMID:20404132)
• rs3184504 in SH2B3 confers susceptibility for multiple sclerosis. (PMID:20508602)
• The SH2B3 784T>C variant could contribute to the pathogenesis of T1 diabetes through impaired immune response that promotes activation and expansion of self-reactive lymphocytes in susceptible individuals. (PMID:20546165)
• Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway (PMID:20560212)
• Association of the polymorphisms of the ERBB3 and SH2B3 genes with type 1 diabetes (PMID:20586186)
• LNK mutation is associated with blast-phase myeloproliferative neoplasms. (PMID:20724988)
• The current study suggests that LNK mutations are part of the “missing link” in the pathogenesis of JAK2 mutation-negative “idiopathic” erythrocytosis or polycythemia vera. (PMID:20843259)
• The Lnk is a negative regulator of PDGFR signaling. (PMID:21310211)
• Lnk is a potential candidate for the modulation of signaling pathways to protect vascular endothelial cells from inflammation in xenotransplantation. (PMID:21496118)
• LNK can also be mutated outside PH and SH2 domains in myeloproliferative neoplasms with and without V617FJAK2 mutation. (PMID:21794913)
• Study suggests that LNK mutations occur in low frequency in human MPN, and can occur in several regions of the LNK gene not only on a pleckstrin homology domain which have been regarded as a hot spot. (PMID:21922527)
• A nonsynonymous LNK polymorphism is associated with idiopathic erythrocytosis. (PMID:21990094)
• SH2B3 inhibits neuronal differentiation of PC12 cells and primary cortical neurons (PMID:22028877)
• Lnk adaptor is an effective regulator of the integrin-mediated signaling pathway that affects endothelial cell adhesion and migration processes. (PMID:22441983)
• Novel associations for hypothyroidism and autoimmune risk loci include SNPs near the SH2B3 gene. (PMID:22493691)
• observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway (PMID:22916186)
• There was an infrequent occurrence of LNK mutations in patients with JAK2 mutation-negative erythrocytosis. (PMID:23812944)
• Thrombotic antiphospholipid syndrome shows strong haplotypic association with SH2B3-ATXN2 locus. (PMID:23844121)
• Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of acute lymphoblastic leukemia (PMID:23908464)
• IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk. (PMID:24297922)
• in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers. (PMID:24704825)
• The single-nucleotide polymorphism in SH2B3 was significantly associated with Hypertension in an Algerian population sample. (PMID:25231511)
• Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer. (PMID:26319099)
• SH2B3 mutations occur infrequently, and exon 8 in SH2B3 may be the most frequent mutational area in BCR-ABL negative myeloproliferative neoplasms patients in Korea. (PMID:26522763)
• the minor allele A of rs3184504 (A vs G, OR = 1.18, 95%CI = 1.12-1.24, P < 0.001) in SH2B3 significantly increased celiac disease susceptibility (Meta-Analysis) (PMID:26535636)
• Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. (PMID:26621817)
• A number of mutations in LNK have been described in a variety of myeloproliferative neoplasms some of which have been demonstrated to cause increased cellular proliferation. (PMID:26660394)
• LNK/SH2B3 is a key driver gene for human hypertension, and alteration of LNK in animal models has a profound effect on inflammation and hypertension. Thus, LNK is a potential therapeutic target for this disease and its devastating consequences. (PMID:26717315)
• results suggest that LNK suppresses IL-7R/JAK/STAT signaling to restrict pro-/pre-B progenitor expansion and leukemia development, providing a pathogenic mechanism and a potential therapeutic approach for B-ALLs with LNK mutations. (PMID:26974155)
• The polymorphisms in LNK gene correlated to the clinical type of myeloproliferative neoplasms regardless of the JAK2 polymorphism. (PMID:27111338)
• In conclusion, germ line LNK mutations rarely occur in familial myeloproliferative neoplasms (MPNs) and do not segregate with the disease phenotype. The findings suggest that mutations in LNK, either germ line or acquired, may cooperate with acquired driver mutations in JAK2, CALR, or MPL to determine disease phenotype in MPNs. (PMID:27216218)
• indicate that IL7RhighSH2B3low expression distinguishes a novel subset of high-risk B-acute lymphoblastic leukemia associated with Ikaros dysfunction (PMID:27322554)
• Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with SH2B3 deficiency. (PMID:27430239)
• Elevated expression of Lnk in polycystic ovary syndrome suggests that Lnk probably plays a role in the development of insulin resistance. (PMID:27459314)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh2b3	ENSDARG00000069958
mus_musculus	Sh2b3	ENSMUSG00000042594
rattus_norvegicus	Sh2b3	ENSRNOG00000028198
drosophila_melanogaster	Lnk	FBGN0028717

Paralogs (2): SH2B2 (ENSG00000160999), SH2B1 (ENSG00000178188)

Protein

Protein identifiers

SH2B adapter protein 3 — Q9UQQ2 (reviewed: Q9UQQ2)

Alternative names: Lymphocyte adapter protein, Lymphocyte-specific adapter protein Lnk, Signal transduction protein Lnk

All UniProt accessions (3): Q9UQQ2, F5GYM4, R4GN84

UniProt curated annotations — full annotation on UniProt →

Function. Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.

Subunit / interactions. Binds to the tyrosine-phosphorylated TCR zeta chain via its SH2 domain.

Tissue specificity. Preferentially expressed by lymphoid cell lines.

Post-translational modifications. Tyrosine phosphorylated by LCK.

Disease relevance. Celiac disease 13 (CELIAC13) [MIM:612011] A multifactorial, chronic disorder of the small intestine caused by intolerance to gluten. It is characterized by immune-mediated enteropathy associated with failed intestinal absorption, and malnutrition. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. Disease susceptibility is associated with variants affecting the gene represented in this entry. Type 1 diabetes mellitus (T1D) [MIM:222100] A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the SH2B adapter family.

RefSeq proteins (2): NP_001278353, NP_005466* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015012	Phe_ZIP	Domain
IPR030523	SH2B	Family
IPR035059	SH2B3_SH2	Domain
IPR036290	Phe_ZIP_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF08916

UniProt features (24 total): region of interest 6, modified residue 5, compositionally biased region 4, sequence variant 4, domain 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQQ2-F1	63.45	0.19

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 (5): 13, 103, 120, 150, 330

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1433559	Regulation of KIT signaling
R-HSA-9706369	Negative regulation of FLT3
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9607240	FLT3 Signaling

MSigDB gene sets: 519 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, CREL_01, GOBP_EMBRYONIC_HEMOPOIESIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_MYELOID_CELL_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_COAGULATION, GOBP_NEGATIVE_REGULATION_OF_PLATELET_ACTIVATION, GOBP_PLATELET_ACTIVATION, GOBP_ERYTHROCYTE_HOMEOSTASIS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN

GO Biological Process (24): neutrophil homeostasis (GO:0001780), negative regulation of cell population proliferation (GO:0008285), embryonic hemopoiesis (GO:0035162), intracellular signal transduction (GO:0035556), monocyte homeostasis (GO:0035702), megakaryocyte development (GO:0035855), cellular response to interleukin-3 (GO:0036016), thrombopoietin-mediated signaling pathway (GO:0038163), negative regulation of MAPK cascade (GO:0043409), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), erythrocyte development (GO:0048821), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), hematopoietic stem cell differentiation (GO:0060218), negative regulation of response to cytokine stimulus (GO:0060761), negative regulation of chemokine-mediated signaling pathway (GO:0070100), negative regulation of platelet aggregation (GO:0090331), negative regulation of Kit signaling pathway (GO:1900235), negative regulation of receptor signaling pathway via STAT (GO:1904893), cellular response to chemokine (GO:1990869), myeloid cell homeostasis (GO:0002262), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), hemopoiesis (GO:0030097), myeloid cell development (GO:0061515)

GO Molecular Function (6): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), stem cell factor receptor binding (GO:0005173), signaling receptor complex adaptor activity (GO:0030159), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515), signaling adaptor activity (GO:0035591)

GO Cellular Component (2): cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Signaling by SCF-KIT	1
FLT3 Signaling	1
Hemostasis	1
Immune System	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
leukocyte homeostasis	2
myeloid cell homeostasis	2
myeloid cell development	2
cellular response to cytokine stimulus	2
chemokine-mediated signaling pathway	2
negative regulation of intracellular signal transduction	2
negative regulation of cytokine-mediated signaling pathway	2
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
hemopoiesis	1
embryonic organ development	1
intracellular anatomical structure	1
signal transduction	1
megakaryocyte differentiation	1
response to interleukin-3	1
MAPK cascade	1
regulation of MAPK cascade	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
negative regulation of receptor signaling pathway via STAT	1
erythrocyte differentiation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
hematopoietic progenitor cell differentiation	1
stem cell differentiation	1
response to cytokine	1
negative regulation of response to stimulus	1
regulation of response to cytokine stimulus	1
negative regulation of G protein-coupled receptor signaling pathway	1
regulation of chemokine-mediated signaling pathway	1
negative regulation of platelet activation	1
negative regulation of homotypic cell-cell adhesion	1
platelet aggregation	1
regulation of platelet aggregation	1
Kit signaling pathway	1
regulation of Kit signaling pathway	1
negative regulation of signal transduction	1
cell surface receptor signaling pathway via STAT	1
regulation of receptor signaling pathway via STAT	1

Protein interactions and networks

STRING

1572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH2B3	JAK2	O60674	976
SH2B3	ASXL1	Q8IXJ9	885
SH2B3	TET2	Q6N021	840
SH2B3	TAGAP	Q8N103	798
SH2B3	THPO	P40225	790
SH2B3	ATXN2	Q99700	765
SH2B3	NAA25	Q14CX7	760
SH2B3	MPL	P40238	757
SH2B3	EZH2	Q15910	745
SH2B3	CLEC16A	Q2KHT3	727
SH2B3	BLTP1	Q2LD37	691
SH2B3	PTPN2	P17706	663
SH2B3	LCK	P06239	663
SH2B3	SETBP1	Q9Y6X0	657
SH2B3	BACH2	Q9BYV9	648

IntAct

19 interactions, top by confidence:

A	B	Type	Score
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
YWHAE	SRSF10	psi-mi:“MI:0914”(association)	0.560
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
HAVCR2	SYK	psi-mi:“MI:0914”(association)	0.460
EGFR	SH2B3	psi-mi:“MI:0407”(direct interaction)	0.440
ERBB2	SH2B3	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B3	EGFR	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B3	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B3	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B3	MET	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B3	Ptpn6	psi-mi:“MI:0914”(association)	0.350
TSC22D4	LANCL1	psi-mi:“MI:0914”(association)	0.350
CHCHD4	PDHX	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): SH2B3 (Two-hybrid), KIT (Reconstituted Complex), ILK (Affinity Capture-Western), SH2B3 (Affinity Capture-Western), SH2B3 (Affinity Capture-MS), LCK (Affinity Capture-Western), SH2B3 (Reconstituted Complex), SH2B3 (Reconstituted Complex), SH2B3 (Reconstituted Complex), SH2B3 (Reconstituted Complex), SH2B3 (Reconstituted Complex), SH2B3 (Reconstituted Complex), GRB2 (Affinity Capture-Western), PLCG1 (Affinity Capture-Western), FLNA (Two-hybrid)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

Diamond homologs: O09039, O14492, O45539, O70142, O88834, P00519, P00520, P00521, P00522, P09760, P10447, P29353, P32577, P41239, P41240, P41241, P41242, P41243, P42679, P42684, P50745, P98077, P98083, Q08CX2, Q0IIE2, Q0VBZ0, Q5M824, Q5R7W7, Q62270, Q62985, Q6S5L8, Q8AY68, Q8BMC3, Q8IPW2, Q91ZM2, Q9H3Y6, Q9JID9, Q9JLM9, Q9NRF2, Q9UQQ2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SH2B3	“down-regulates quantity by repression”	BCL2L1	“transcriptional regulation”
LCK	up-regulates	SH2B3	phosphorylation
ZAP70	up-regulates	SH2B3	phosphorylation
SH2B3	“down-regulates activity”	JAK2	binding
“pazopanib hydrochloride”	“down-regulates activity”	SH2B3	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Constitutive Signaling by Aberrant PI3K in Cancer	5	42.3×	1e-05
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	32.3×	3e-05
RAF/MAP kinase cascade	6	24.4×	1e-05
PIP3 activates AKT signaling	5	22.3×	4e-05
Infectious disease	5	8.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	5	22.4×	7e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — MDS.

Clinical variants and AI predictions

ClinVar

1035 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	631
Likely benign	361
Benign	17

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1686181	NM_005475.3(SH2B3):c.1A>G (p.Met1Val)	Pathogenic
1805838	NM_005475.3(SH2B3):c.1228del (p.Gly409_Ile410insTer)	Pathogenic
30444	NM_005475.3(SH2B3):c.603_607del (p.Arg202fs)	Pathogenic
4531382	NM_005475.3(SH2B3):c.1148dup (p.Pro383_Asp384insTer)	Pathogenic
3065048	NM_005475.3(SH2B3):c.1566dup (p.Glu523fs)	Likely pathogenic

SpliceAI

1653 predictions. Top by Δscore:

Variant	Effect	Δscore
12:111446203:G:GT	donor_gain	1.0000
12:111447032:GG:G	donor_gain	1.0000
12:111447033:GG:G	donor_gain	1.0000
12:111447327:CAGG:C	acceptor_loss	1.0000
12:111447328:AGGTG:A	acceptor_loss	1.0000
12:111447505:GGAA:G	donor_gain	1.0000
12:111447506:GAA:G	donor_gain	1.0000
12:111447540:CCAAG:C	donor_loss	1.0000
12:111447541:CAAGG:C	donor_loss	1.0000
12:111447542:AAGG:A	donor_loss	1.0000
12:111447543:AGG:A	donor_loss	1.0000
12:111447545:G:C	donor_loss	1.0000
12:111447546:T:G	donor_loss	1.0000
12:111447654:A:AG	acceptor_gain	1.0000
12:111447655:G:GG	acceptor_gain	1.0000
12:111447655:GC:G	acceptor_gain	1.0000
12:111447655:GCA:G	acceptor_gain	1.0000
12:111447799:C:G	donor_gain	1.0000
12:111406274:TCAGG:T	donor_loss	0.9900
12:111406276:AGGT:A	donor_loss	0.9900
12:111406277:GGT:G	donor_loss	0.9900
12:111406278:GT:G	donor_loss	0.9900
12:111406279:T:A	donor_loss	0.9900
12:111418873:CCAAG:C	donor_gain	0.9900
12:111418874:CAAG:C	donor_gain	0.9900
12:111418875:AAG:A	donor_gain	0.9900
12:111418876:AG:A	donor_gain	0.9900
12:111418877:GG:G	donor_gain	0.9900
12:111418878:G:GG	donor_gain	0.9900
12:111446092:C:CA	acceptor_gain	0.9900

AlphaMissense

3673 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:111418246:C:A	A34D	0.999
12:111418258:C:A	A38D	0.999
12:111418345:T:C	F67S	0.999
12:111418357:T:C	F71S	0.999
12:111447398:T:A	W364R	0.999
12:111447398:T:C	W364R	0.999
12:111447516:T:C	L403P	0.999
12:111447660:T:C	L414P	0.999
12:111447741:T:C	F441S	0.999
12:111447756:T:C	I446T	0.999
12:111418231:T:C	F29S	0.998
12:111418267:T:C	L41P	0.998
12:111418278:T:G	Y45D	0.998
12:111418344:T:C	F67L	0.998
12:111418346:C:A	F67L	0.998
12:111418346:C:G	F67L	0.998
12:111418369:T:C	F75S	0.998
12:111447401:T:C	F365L	0.998
12:111447403:C:A	F365L	0.998
12:111447403:C:G	F365L	0.998
12:111447441:T:A	V378D	0.998
12:111447468:G:A	G387E	0.998
12:111447473:T:C	F389L	0.998
12:111447474:T:C	F389S	0.998
12:111447475:C:A	F389L	0.998
12:111447475:C:G	F389L	0.998
12:111447477:T:C	L390P	0.998
12:111447516:T:A	L403H	0.998
12:111447521:T:C	F405L	0.998
12:111447522:T:C	F405S	0.998

dbSNP variants (sampled 300 via entrez): RS1000024393 (12:111412736 T>C), RS1000052739 (12:111405512 G>A,T), RS1000104083 (12:111411743 C>T), RS1000134269 (12:111431548 G>T), RS1000168214 (12:111413486 A>G), RS1000172488 (12:111436158 C>T), RS1000218363 (12:111424798 A>G), RS1000275507 (12:111431138 C>G), RS1000305783 (12:111411527 C>G,T), RS1000306833 (12:111430131 C>T), RS1000392996 (12:111418891 G>A,C), RS1000472622 (12:111430054 C>T), RS1000508115 (12:111417851 A>G), RS1000607842 (12:111429814 A>G), RS1000755642 (12:111423699 G>A)

Disease associations

OMIM: gene MIM:605093 | disease phenotypes: MIM:133100, MIM:187950, MIM:254450, MIM:607785, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
SH2B3-related immune system disorder	Definitive	Semidominant
syndromic disease	Strong	Autosomal recessive
acute lymphoblastic leukemia	Moderate	Autosomal recessive
growth retardation-mild developmental delay-chronic hepatitis syndrome	Supportive	Autosomal recessive
primary familial polycythemia due to EPO receptor mutation	No Known Disease Relationship	Unknown
schizophrenia	No Known Disease Relationship	Unknown
thrombocythemia 1	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
SH2B3-related immune system disorder	Definitive	SD

Mondo (14): primary familial polycythemia due to EPO receptor mutation (MONDO:0007572), thrombocythemia 1 (MONDO:0008554), primary myelofibrosis (MONDO:0009692), thrombocytosis disease (MONDO:0002249), hereditary neoplastic syndrome (MONDO:0015356), familial myelofibrosis (MONDO:0023119), hepatoblastoma (MONDO:0018666), juvenile myelomonocytic leukemia (MONDO:0011908), plasma cell myeloma (MONDO:0009693), acute lymphoblastic leukemia (MONDO:0004967), SH2B3-related immune system disorder (MONDO:1060195), schizophrenia (MONDO:0005090), growth retardation-mild developmental delay-chronic hepatitis syndrome (MONDO:0018317), syndromic disease (MONDO:0002254)

Orphanet (7): Primary myelofibrosis (Orphanet:824), Primary familial polycythemia (Orphanet:90042), Inherited cancer-predisposing syndrome (Orphanet:140162), Hepatoblastoma (Orphanet:449), Juvenile myelomonocytic leukemia (Orphanet:86834), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000505	Visual impairment
HP:0000822	Hypertension
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000980	Pallor
HP:0001050	Plethora
HP:0001342	Cerebral hemorrhage
HP:0001442	Typified by somatic mosaicism
HP:0001658	Myocardial infarction
HP:0001744	Splenomegaly
HP:0001872	Abnormality of thrombocytes
HP:0001892	Abnormal bleeding
HP:0001894	Thrombocytosis
HP:0001898	Increased red blood cell mass
HP:0001899	Increased hematocrit
HP:0001900	Increased circulating hemoglobin concentration
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0001978	Extramedullary hematopoiesis
HP:0002076	Migraine
HP:0002240	Hepatomegaly
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002326	Transient ischemic attack
HP:0002488	Acute leukemia
HP:0002641	Peripheral thrombosis
HP:0002863	Myelodysplasia
HP:0002875	Exertional dyspnea
HP:0003010	Prolonged bleeding time

GWAS associations

216 associations (top):

Study	Trait	p-value
GCST000043_1	Type 1 diabetes	2.000000e-14
GCST000157_7	Celiac disease	8.000000e-08
GCST000339_2	Eosinophil count	7.000000e-19
GCST000392_3	Type 1 diabetes	3.000000e-27
GCST000393_7	Systolic blood pressure	5.000000e-09
GCST000394_4	Diastolic blood pressure	3.000000e-18
GCST000396_5	Diastolic blood pressure	3.000000e-14
GCST000502_1	Hematocrit	1.000000e-12
GCST000580_6	Platelet count	5.000000e-19
GCST000612_36	Celiac disease	7.000000e-21
GCST000847_3	Retinal vascular caliber	2.000000e-13
GCST000987_1	Celiac disease or Rheumatoid arthritis	3.000000e-19
GCST000998_14	Coronary heart disease	6.000000e-06
GCST001191_16	Type 1 diabetes	2.000000e-38
GCST001228_3	Diastolic blood pressure	4.000000e-25
GCST001337_37	Platelet count	1.000000e-26
GCST001474_12	Hypothyroidism	3.000000e-12
GCST001509_2	Vitiligo	4.000000e-18
GCST001765_12	Red blood cell traits	4.000000e-19
GCST001863_1	Beta-2 microglubulin plasma levels	3.000000e-08
GCST002186_6	Platelet count	5.000000e-11
GCST002286_4	Ischemic stroke	6.000000e-08
GCST002287_6	Coronary artery disease or ischemic stroke	4.000000e-14
GCST002289_20	Coronary artery disease	9.000000e-07
GCST002290_6	Coronary artery disease or large artery stroke	3.000000e-10
GCST002318_56	Rheumatoid arthritis	7.000000e-09
GCST002373_2	Thyroid peroxidase antibody levels	1.000000e-07
GCST002378_2	Thyroid peroxidase antibody positivity	1.000000e-09
GCST002423_3	Autoimmune hepatitis type-1	8.000000e-08
GCST002504_1	Peripheral artery disease	6.000000e-07

EFO canonical traits (51, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004348	hematocrit
EFO:0004309	platelet count
EFO:0004731	eye measurement
EFO:0004509	hemoglobin measurement
EFO:0005197	beta-2 microglobulin measurement
EFO:0004230	endometrial neoplasm
EFO:0008393	reaction time measurement
EFO:1001515	ovarian endometrioid carcinoma
EFO:1001516	ovarian serous carcinoma
EFO:0007924	tonsillectomy risk measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count
EFO:0007985	platelet crit
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007986	reticulocyte count
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0004340	body mass index
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0006527	smoking status measurement
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D055728	Primary Myelofibrosis	C15.378.190.636.765
D013577	Syndrome	C23.550.288.500
D013922	Thrombocytosis	C15.378.140.860; C15.378.190.636.860
C536848	Familial myelofibrosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3184504	Efficacy	3	candesartan	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3184504	SH2B3	3	3.00	1	candesartan

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, increases methylation, affects cotreatment	8
Cyclosporine	increases expression	4
Cisplatin	affects response to substance, increases expression	3
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	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
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
prothioconazole	increases 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	decreases expression	1
Oxaliplatin	decreases expression	1
Temozolomide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114348	PHASE4	COMPLETED	ALL-REZ BFM 2002: Multi-Center Study for Children With Relapsed Acute Lymphoblastic Leukemia
NCT00192673	PHASE4	UNKNOWN	Poly(Ethylene Glycol)(PEG)-Asparaginase During Two Treatment Courses
NCT00222612	PHASE4	UNKNOWN	Medical Research Council (MRC) Working Party on Leukaemia in Children UK National Acute Lymphoblastic Leukaemia (ALL) Trial: UKALL 2003
NCT00411541	PHASE4	COMPLETED	Pulses of Vincristine and Dexamethasone in BFM Protocols for Children With Acute Lymphoblastic Leukemia
NCT00494897	PHASE4	COMPLETED	PETHEMA LAL-RI/96: Treatment for Patients With Standard Risk Acute Lymphoblastic Leukemia
NCT00526175	PHASE4	COMPLETED	LAL-BR/2001: Study Treatment to Low Risk ALL
NCT00526305	PHASE4	COMPLETED	LAL-Ph-2000: Treatment of Acute Lymphoblastic Leukemia Chromosome Philadelphia Positive
NCT00526409	PHASE4	COMPLETED	LAL-AR-N-2005:Study Treatment for Children High Risk Acute Lymphoblastic Leukemia
NCT00576472	PHASE4	COMPLETED	Learning Impairments Among Survivors of Childhood Cancer
NCT00797810	PHASE4	UNKNOWN	Intensification Therapy of Mature B-ALL, Burkitt and Burkitt Like and Other High Grade Non-Hodgkin’s Lymphoma in Adults
NCT00846703	PHASE4	UNKNOWN	The GD-2008 ALL Protocol for Childhood Acute Lymphoblastic Leukemia
NCT00853008	PHASE4	COMPLETED	Treatment of High Risk Adult Acute Lymphoblastic Leukemia
NCT01358201	PHASE4	UNKNOWN	PETHEMA LAL-07FRAIL: All Treatment In Fragile Patients Ph’ Negative Over 55 Years
NCT01358253	PHASE4	COMPLETED	Rituximab Plus Chemotherapy for CD20+ Adult Acute Lymphoblastic Leukemia
NCT01366898	PHASE4	UNKNOWN	Protocol For the Treatment Acute Lymphoblastic Leukemia With Ph ‘Negative in Elderly Patients (> 55 Years)
NCT01735955	PHASE4	COMPLETED	Study to Allow Access to Nilotinib for Patients Who Are on Nilotinib Treatment in a Novartis-sponsored Study
NCT01873807	PHASE4	UNKNOWN	HD-Idarubicin/Etoposide Intensified Conditioning Regimen Allo-HSCT for Adult ALL
NCT01906671	PHASE4	UNKNOWN	Study on Two Different Formulations of 6-mercaptopurine. Tablet Versus Oral Liquid
NCT02447718	PHASE4	COMPLETED	Vaccinating Children After Chemotherapy
NCT02670564	PHASE4	UNKNOWN	ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)
NCT02894645	PHASE4	UNKNOWN	Malaysia-Singapore Acute Lymphoblastic Leukemia 2010 Study
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT02953730	PHASE4	COMPLETED	The Study on the Pharmacokinetics of PEG-rhG-CSF in Children and Adolescents
NCT03677596	PHASE4	COMPLETED	A Study Of Two Inotuzumab Ozogamicin Doses in Relapsed/ Refractory Acute Lymphoblastic Leukemia Transplant Eligible Patients
NCT03920813	PHASE4	UNKNOWN	Determinants of Mercaptopurine Toxicity in Paediatric Acute Lymphoblastic Leukemia Maintenance Therapy
NCT05133310	PHASE4	UNKNOWN	Effect of Simvastatin on Sepsis and Febrile Neutropenia in Patients With Acute Lymphoblastic Leukemia
NCT05687032	PHASE4	COMPLETED	A Study of Inotuzumab Ozogamicin in Chinese Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia
NCT06289673	PHASE4	RECRUITING	Identification of Necessary Information for Treatment Induction in Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma
NCT06918054	PHASE4	RECRUITING	Hepatoprotective for Children and Adolescent With Acute Lymphoblastic Leukemia
NCT06918080	PHASE4	ACTIVE_NOT_RECRUITING	Hepatoprotective Measures for Children at High Risk of NAFLD
NCT07016165	PHASE4	RECRUITING	Ciprofloxacin vs Ceftazidime for Empirical Treatment of High-Risk Neutropenic Fever in Children With Hematologic Malignancies
NCT07320534	PHASE4	NOT_YET_RECRUITING	Levofloxacin Prophylaxis to Prevent First Febrile Neutropenia in Pediatric ALL During Induction Phase
NCT01558739	PHASE4	COMPLETED	Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)
NCT02386800	PHASE4	ACTIVE_NOT_RECRUITING	CINC424A2X01B Rollover Protocol
NCT00075725	PHASE3	COMPLETED	Dexamethasone Compared With Prednisone During Induction Therapy and Methotrexate With or Without Leucovorin During Maintenance Therapy in Treating Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia
NCT00103285	PHASE3	COMPLETED	Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
NCT00131027	PHASE3	UNKNOWN	High-Dose Methotrexate (MTX) for Adult Acute Lymphoblastic Leukemia (ALL)
NCT00137111	PHASE3	COMPLETED	Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
NCT00152139	PHASE3	COMPLETED	Stem Cell Transplantation for Patients With Hematologic Malignancies
NCT00165087	PHASE3	TERMINATED	Treatment of Childhood Acute Lymphoblastic Leukemia