SETBP1

Chr 18AD

SET binding protein 1

Also known as: MRD29, SEB

NCBI Gene: 26040 ENSG00000152217 UniProt: Q9Y6X0 OMIM: 611060

The protein binds the SET nuclear oncogene and regulates DNA replication through its SET-binding region and ski homology domain. Mutations cause Schinzel-Giedion midface retraction syndrome and autosomal dominant intellectual developmental disorder through loss-of-function mechanisms. The inheritance pattern is autosomal dominant with extremely high intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.112 OMIM phenotypes

Clinical Summary— SETBP1

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Gene-Disease Validity (ClinGen)

Schinzel-Giedion syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — 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

0.11LOEUF

pLI 1.000

Z-score 5.95

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

1.10Z-score

OE missense 0.90 (0.84–0.95)

776 obs / 866.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.02 (0.01–0.11)

0≤0.351.4

Missense OE0.90 (0.84–0.95)

0≤0.61.4

Synonymous OE1.07

0≤1.21.6

LoF obs/exp: 1 / 43.3Missense obs/exp: 776 / 866.8Syn Z: -1.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSETBP1-related developmental and expressive language delayLOFAD

definitiveSETBP1-related Schinzel-Giedion midface retraction syndromeGOFAD

0.2199th %ile

GOF

0.2597th %ile

LOF

0.90top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.11

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNAs rare 18q interstitial deletions affecting multiple genes including SETBP1 correlate with a milder phenotype, including minor physical anomalies and developmental and expressive speech delay, mutations in SETBP1 are thought to result in a gain-of-function or a dominant-negative effect.PMID:21037274

GOFThere is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.PMID:29666323

LOFClinical delineation of SETBP1 haploinsufficiency disorder.PMID:33867525

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