SH2B3

protein-coding

SH2B adaptor protein 3, the group of Pleckstrin homology domain containing|SH2 domain containing

Gene summary

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. [provided by RefSeq, Apr 2014]

MANE transcript

NM_005475.3

Inheritance

AR, SD

ClinVar variants

P:8U:748B:419

Top phenotype

SH2B3-related immune system disorder

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr12:111,405,923-111,451,623

External References & Databases

Ensembl (ENSG00000111252)

Transcript & Mutation Effects

hg38 • Region Span ~45.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

acute lymphoblastic leukemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0004967

Submitter: Ambry Genetics

growth retardation-mild developmental delay-chronic hepatitis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018317

Submitter: Orphanet

SH2B3-related immune system disorderDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:1060195

Submitter: ClinGen

SH2B3 was first reported in relation to AR myeloproliferation and autoimmunity in 2013 (Perez-Garcia et al. PMID: 23908464). SH2B3 functions as a negative regulator of multiple cytokine and growth factor receptor signaling pathways. The SH2B3 protein directly binds JAK via its SH2 domain and plays a relevant role in hematopoiesis. Both autosomal recessive and autosomal dominant modes of inheritance were described, presenting a semidominant pattern. The disease onset typically occurs in the neonatal period or within the first few months of life. Clinical manifestations are characterized by a myeloproliferative disorder, with variable features including hepatosplenomegaly, thrombocytopenia, monocytosis, juvenile myelomonocytic leukemia, and autoimmune disease. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two: SH2B3-related myeloproliferation and autoimmunity and Juvenile myelomonocytic leukemia (JMML) predisposition.The split curation for autosomal recessive JMML predisposition is curated separately. Sixteen variants (missense, nonsense, and frameshift) have been reported in 16 probands in five publications (PMIDs: 38152053, 37981895, 37206266, 40481232, 23908464) and are included in this curation. In the context of a semidominant mode of inheritance, probands have been identified harboring homozygous (n = 10) and heterozygous variants (n = 6). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models, gene expression analysis, and biochemical studies (PMIDs: 23908464 and 37206266). Experiments have been conducted to evaluate gene expression in patient-derived cells, altered biochemical function, phenotype rescue in patient derived cells, and the effects of zebrafish sh2b3 knockdown showing a disease‑related phenotype. In summary, there is definitive evidence supporting the relationship between SH2B3 and semidominant SH2B3-related immune system disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date August 12th, 2025 (SOP Version 11).

primary familial polycythemia due to EPO receptor mutationNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007572

Submitter: Labcorp Genetics (formerly Invitae)

thrombocythemia 1NO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0008554

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH2B3 variants in ClinVar

16 Conditions Cataloged

Inborn genetic diseasesTotal: 1113

not providedTotal: 78

SH2B3-related disorderTotal: 22

not specifiedTotal: 18

Myeloproliferative neoplasmTotal: 12

Primary myelofibrosisTotal: 8

Primary familial polycythemia due to EPO receptor mutationTotal: 6

Thrombocythemia 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005475.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	390 clinvar		392
missense		1 clinvar	737 clinvar	24 clinvar	5 clinvar	767
nonsense			5 clinvar			5
start loss	1 clinvar					1
frameshift	4 clinvar	2 clinvar	3 clinvar			9
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	3	748	414	5	1175

Highest pathogenic variant AF is 0.00034914032

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005475.3	RefSeq	NP_005466.1	7	MANE Select
ENST00000341259.7	Ensembl	ENSP00000345492.2	7	MANE Select
NM_001291424.1	RefSeq	NP_001278353.1	7	Standard
ENST00000538307.1	Ensembl	ENSP00000440597.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
TYROBP Causal Network
T-Cell antigen Receptor (TCR) Signaling Pathway
Signal Transduction
Factors involved in megakaryocyte development and platelet production

Biological Process

transmembrane receptor protein tyrosine kinase signaling pathway
blood coagulation
positive regulation of signal transduction
cell differentiation
embryonic hemopoiesis

Molecular Function

transmembrane receptor protein tyrosine kinase adaptor activity
protein binding

Cellular Component

cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341259
Coding exons: 7
Length: 45676
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125747
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.415	301	322	0.935	0.0000233	3559
Missense (PolyPhen)		122	138.12	0.88326		1508
Synonymous	1.93	120	150	0.800	0.0000116	1259
Loss of Function	2.24	10	21.1	0.473	0.00000115	226

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.00014	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase. {ECO:0000250}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:18311140}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [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. {ECO:0000269|PubMed:17554260}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.358

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.679

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium