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.

GeneReviews OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 58MIM #618106

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · intellectual disability · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

85521

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — SET

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

306 rare PASS variants

Rare truncating (LoF)

1 in 800

83 rare PASS variants

Rare synonymous (reference)

1 in 350

171 rare PASS variants

Rare missense and truncating variants are carried at similar rates in SET; this gene does not show strong loss-of-function constraint by this measure. 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 270	1 in 430
South Asian	~43k	1 in 150	1 in 330
Remaining (unassigned)	~30k	1 in 170	1 in 580
European (Finnish)	~27k	1 in 330	1 in 580
Admixed American	~22k	1 in 160	1 in 560
African / African American	~21k	1 in 320	1 in 650
East Asian	~20k	1 in 200	1 in 630
Ashkenazi Jewish	~13k	1 in 1,900	1 in 2,200
Middle Eastern	~2,884	1 in 350	≈ 1 in 620

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): 3 of 8 coding exons well covered in gnomAD exomes; exons 1, 2, 5, 7, 8 marginal. Genomes: 7 of 8 (exon 1 below).? see exons ↓