SET

Chr 9

SET nuclear proto-oncogene

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

NCBI Gene: 6418 ENSG00000119335 UniProt: Q01105

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.18

Clinical Summary— SET

🧬

Gene-Disease Validity (ClinGen)

intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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.

📋

ClinVar Variants

42 unique Pathogenic / Likely Pathogenic· 49 VUS of 137 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SET

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.18LOEUF

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 OE?0.00 (0.00–0.18)

0≤0.351.4

Missense OE?0.38 (0.30–0.47)

0≤0.61.4

Synonymous OE?1.10

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

This gene — mechanism propensity

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 · 76% of P/LP variants are LoF · LOEUF 0.18 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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-me2

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

References

ClinVar Variant Classifications

137 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic19

VUS49

Likely Benign23

Benign6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	1	2	0	23
Likely Pathogenic	12	6	1	0	19
VUS	3	42	4	0	49
Likely Benign	0	7	5	11	23
Benign	0	0	5	1	6
Total	35	56	17	12	120

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap SET — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SET · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — SET

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Rare DiseasesOphthalmology

Identification of Cellular Biomarkers of Rare Eye Diseases in Adults

RECRUITING

NCT07063719Phase NAInstitut National de la Santé Et de la Recherche Médicale, FranceStarted 2026-06-01

Ophthalmological visitQuestionnairesBlood sample collection

Solid Tumor, Unspecified, AdultHaematological Malignancy

Proseq Cancer: Genomic Profiling in Patients With Incurable Cancer in Search for Targeted Treatment

RECRUITING

NCT05695638Morten LadekarlStarted 2020-07-01

Cystic Fibrosis

Correction of Nonsense Mutations in Cystic Fibrosis

RECRUITING

NCT03670472University Hospital, LilleStarted 2016-02-03

smear of nasal fossae

Wilson's Disease

Multifaceted Assessment of Patients With Wilson's Disease in a Low-Resource Setting in Upper Egypt: Service Integration, Psychosocial Burden, Dietary Practices, and the Geo-Spatial Disease Map

NOT YET RECRUITING

NCT07241832Assiut UniversityStarted 2025-12-01

KAB-pB Scores

Urinary Tract Infections

DIagnoSing Care hOme UTI Study

RECRUITING

NCT05880329University of SouthamptonStarted 2023-09-01

Candidate POCTs for detecting UTI

Validation Study of Molecular Diagnostic SystemDevelopment of Reporting System for Molecular DiagnosisIncorporate Molecular Diagnosis Into Diagnostic Standards

Diagnostic and Therapeutic Applications in Microarrays in Organ Transplantation

RECRUITING

NCT01299168University of AlbertaStarted 2011-05