SH2B1

Chr 16

SH2B adaptor protein 1

Also known as: PSM, SH2B

NCBI Gene: 25970 ENSG00000178188 UniProt: Q9NRF2

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.

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]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in SH2B1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 54

1,106 rare PASS variants

Rare truncating (LoF)

1 in 1,500

92 rare PASS variants

Rare synonymous (reference)

1 in 120

436 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SH2B1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 64	1 in 1,700
South Asian	~43k	1 in 46	1 in 2,600
Remaining (unassigned)	~30k	1 in 43	1 in 590
European (Finnish)	~27k	1 in 220	1 in 700
Admixed American	~22k	1 in 46	1 in 4,400
African / African American	~21k	1 in 51	≈ 1 in 4,500
East Asian	~20k	1 in 49	1 in 1,100
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 3,100
Middle Eastern	~2,884	1 in 52	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: 7 of 8 (exon 5 below).? see exons ↓