SH2B1

Chr 16

SH2B adaptor protein 1

Also known as: PSM, SH2B

NCBI Gene: 25970 ENSG00000178188 UniProt: Q9NRF2 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

272 VUS of 431 total submissions

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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 OE?0.14 (0.07–0.32)

0≤0.351.4

Missense OE?0.91 (0.84–0.99)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 28.4Missense obs/exp: 415 / 456.5Syn Z: 0.29

This gene — mechanism propensity

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

431 submitted variants in ClinVar

ClinVar

Classification Summary

VUS272

Likely Benign131

Benign9

Conflicting8

272

VUS

131

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	13	255	1	3	272
Likely Benign	0	7	17	107	131
Benign	0	2	4	3	9
Conflicting	—				8
Total	13	264	22	113	420

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

View in ClinVar →

118 pathogenic / likely-pathogenic (of 160) ClinVar copy-number / structural variants overlap SH2B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →