SET

Chr 9AD

SET nuclear proto-oncogene

Also known as: 2PP2A, I2PP2A, IGAAD, IPP2A2, MRD58, PHAPII, TAF-I, TAF-IBETA

NCBI Gene: 6418 ENSG00000119335 UniProt: Q01105 OMIM: 600960

This protein inhibits histone acetyltransferases and serves as a histone chaperone, regulating chromatin structure and gene transcription while also functioning in apoptosis regulation and DNA replication. Mutations cause autosomal dominant intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 0.996, LOEUF 0.183), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.181 OMIM phenotype

Clinical Summary— SET

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Gene-Disease Validity (ClinGen)

intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

12 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.18LOEUF

pLI 0.996

Z-score 3.74

OE 0.00 (0.00–0.18)

Highly constrained

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

Missense Constraint

2.66Z-score

OE missense 0.38 (0.30–0.47)

55 obs / 145.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.18)

0≤0.351.4

Missense OE0.38 (0.30–0.47)

0≤0.61.4

Synonymous OE1.10

0≤1.21.6

LoF obs/exp: 0 / 16.3Missense obs/exp: 55 / 145.1Syn Z: -0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSET-related intellectual developmental disorderLOFAD

0.3892th %ile

GOF

0.3590th %ile

LOF

0.63top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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.

LOF1 literature citation · LOEUF 0.18

GOF1 literature citation

Literature Evidence

GOFIts catalytic activity is closely correlated with the stability of PRC2, and somatic activating mutation of EZH2 Y641F within the catalytic SET domain drives tumor aggressiveness, drug resistance, and poor prognosis.PMID:32394628

LOFHaploinsufficiency due to SET mutations is a likely pathogenic mechanism in the development of ID. The frameshift mutations identified in this study lead to a premature termination codon in exons 2, 4, and 6 respectively, which would likely render the mutant SET transcript susceptible to nonsense-mePMID:29688601

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