SH2B1

Chr 16

SH2B adaptor protein 1

Also known as: PSM, SH2B

NCBI Gene: 25970ENSG00000178188UniProt: Q9NRF2

This gene encodes a member of the SH2-domain containing mediators family. The encoded protein mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular transformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

589
ClinVar variants
118
Pathogenic / LP
0.97
pLI score· haploinsufficient
6
Active trials
Clinical Summary— SH2B1
⚡
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.
📋
ClinVar Variants
118 Pathogenic / Likely Pathogenic· 307 VUS of 589 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.69Z-score
OE missense 0.91 (0.84–0.99)
415 obs / 456.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.14 (0.07–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.84–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 4 / 28.4Missense obs/exp: 415 / 456.5Syn Z: 0.29

ClinVar Variant Classifications

589 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic108
Likely Pathogenic10
VUS307
Likely Benign131
Benign10
Conflicting10
108
Pathogenic
10
Likely Pathogenic
307
VUS
131
Likely Benign
10
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
108
0
108
Likely Pathogenic
0
0
10
0
10
VUS
12
246
46
3
307
Likely Benign
0
7
18
106
131
Benign
0
2
4
4
10
Conflicting
—10
Total12255186113576

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Speliotes EK et al.·Nat Genet
2010
Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3.
Raposo M et al.·Brain
2023
Genetic and structural variation in the SH2B1 gene in the Belgian population.
Aerts E et al.·Mol Genet Metab
2015
Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: Experience from two centres.
Morandi A et al.·Pediatr Obes
2024
Effects of Rare Coding Variants in Severe Early-Onset Obesity Genes in the Population-Based UK Biobank Study.
Jia RY et al.·J Clin Endocrinol Metab
2025
SH2B1 is critical for the regulation of cardiac remodelling in response to pressure overload.
Wu G et al.·Cardiovasc Res
2015Functional
Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services.
Roberts JL et al.·Gene
2014
SH2B1 variants as potential causes of non-syndromic monogenic obesity in a Brazilian cohort.
da Fonseca ACP et al.·Eat Weight Disord
2022Cohort
Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance.
Argetsinger LS et al.·Endocrinology
2023
Clinical epigenetics and restoring of metabolic health in severely obese patients undergoing batriatric and metabolic surgery.
Faenza M et al.·Updates Surg
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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
2025🔓 Open 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
Endogenous SH2B1 protein localizes to lamellipodia and filopodia: platinum replica electron-microscopy study.
Diakonova M et al.·MicroPubl Biol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Obesity

Intensive Weight Loss Intervention Versus Usual Care for Adults With Obesity

ACTIVE NOT RECRUITING
NCT06321432Phase NACarsten DirksenStarted 2024-06-05
Intensive weight loss interventionUsual care
Monogenic Obesity

Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice

RECRUITING
NCT07302802Prof. Dr. Martin WabitschStarted 2025-12-01
Semaglutide (administered by PDS290 pen-injector)
Obesity

Intensive Weight Loss Intervention Versus Bariatric Surgery for Adults With Severe and Complex Obesity: the LightBAR Randomised Trial

RECRUITING
NCT06309238Phase NACarsten DirksenStarted 2024-05-08
Intensive weight loss interventionBariatric surgery
ObesityGenetic Obesity

EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway

ACTIVE NOT RECRUITING
NCT05093634Phase PHASE3Rhythm Pharmaceuticals, Inc.Started 2021-12-10
SetmelanotidePlacebo
Obesity

Intensive Weight Loss Intervention Versus Usual Care for Adults With Severe and Complex Obesity

RECRUITING
NCT06321458Phase NACarsten DirksenStarted 2024-04-29
Intensive weight loss interventionUsual care
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools