SH2B1

Chr 16

SH2B adaptor protein 1

Also known as: PSM, SH2B

NCBI Gene: 25970ENSG00000178188UniProt: Q9NRF2OMIM: 608937

The SH2B1 protein functions as an adapter that enhances signaling through multiple receptor tyrosine kinases and JAK2, including pathways for growth hormone, leptin, insulin, and neurotrophic factors. Mutations cause autosomal dominant obesity, intellectual disability, and behavioral problems, typically manifesting in early childhood with severe hyperphagia and rapid weight gain. This condition affects metabolic, neurological, and behavioral systems due to disrupted leptin and growth factor signaling pathways.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismLOEUF 0.32
Clinical Summary— SH2B1
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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
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Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.32LOEUF
pLI 0.969
Z-score 4.24
OE 0.14 (0.07–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
0.69Z-score
OE missense 0.91 (0.84–0.99)
415 obs / 456.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.14 (0.07–0.32)
0≤0.351.4
Missense OE0.91 (0.84–0.99)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 4 / 28.4Missense obs/exp: 415 / 456.5Syn Z: 0.29
DN
0.3793th %ile
GOF
0.5759th %ile
LOF
0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.32

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SH2B1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Genetic distribution of selected obesity-related SNVs in the FTO, DRD2, MC4R, FABP2, ADRB2, and SH2B1 genes in a Mexico city population.
Perezcano C et al.·Front Genet
2026
Prmt1-mediated methylation of Ddx17 promotes osteoblast differentiation via regulating the alternative splicing of Sh2b1.
Jiang X et al.·Bone
2026
Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis.
Zhang Z et al.·Clin Transl Med
2025Open Access
A case-control study on SH2B1 gene variants in obesity and obstructive sleep apnea severity: genetic risk factors in the leptin signaling pathway.
Kuccukturk S et al.·Expert Rev Endocrinol Metab
2025
Identification of βIIΣ1-Spectrin as a Binding Partner of the GH-regulated Human Obesity Scaffold Protein SH2B1.
Lanning NJ et al.·Endocrinology
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients