SETD2

Chr 3AD

SET domain containing 2, histone lysine methyltransferase

Also known as: HBP231, HIF-1, HIP-1, HSPC069, HYPB, KMT3A, LLS, MRD70

NCBI Gene: 29072ENSG00000181555UniProt: Q9BYW2

Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 70MIM #620157
AD
Luscan-Lumish syndromeMIM #616831
AD
Rabin-Pappas syndromeMIM #620155
AD
UniProtRenal cell carcinoma
UniProtLeukemia, acute lymphoblastic
UniProtLeukemia, acute myelogenous
463
ClinVar variants
30
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— SETD2
🧬
Gene-Disease Validity (ClinGen)
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome · ADStrong

Strong evidence — appropriate for clinical testing

2 total gene-disease associations curated

⚡
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
30 Pathogenic / Likely Pathogenic· 258 VUS of 463 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 1.000
Z-score 8.30
OE 0.13 (0.09–0.21)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.05Z-score
OE missense 0.76 (0.72–0.81)
1011 obs / 1322.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.09–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.72–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 14 / 106.4Missense obs/exp: 1011 / 1322.7Syn Z: 0.45

ClinVar Variant Classifications

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic11
VUS258
Likely Benign129
Benign26
Conflicting20
19
Pathogenic
11
Likely Pathogenic
258
VUS
129
Likely Benign
26
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
1
10
0
19
Likely Pathogenic
4
5
2
0
11
VUS
3
241
14
0
258
Likely Benign
0
52
19
58
129
Benign
0
16
6
4
26
Conflicting
—20
Total153155162463

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

View in ClinVar →

Protein Context — Lollipop Plot

SETD2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SETD2-related Rabin-Pappas syndrome

moderate
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

SETD2-related overgrowth syndrome (Luscan-Lumish syndrome)

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 70

MIM #620157

Molecular basis of disorder known

Autosomal dominant

Luscan-Lumish syndrome

MIM #616831

Molecular basis of disorder known

Autosomal dominant

Rabin-Pappas syndrome

MIM #620155

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SETD2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.
Niu N et al.·Cancer Cell
2024
Histone H3.3 phosphorylation amplifies stimulation-induced transcription.
Armache A et al.·Nature
2020
Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.
Lee S et al.·Hum Mol Genet
2023Review
Contributions of Rare Gene Variants to Familial and Sporadic FSGS.
Wang M et al.·J Am Soc Nephrol
2019
Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
Philip PA et al.·Clin Cancer Res
2022Cohort
Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.
Parra A et al.·Genes (Basel)
2023Review
H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis.
Shao R et al.·Cell Death Differ
2024
SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.
Rao H et al.·Nat Commun
2023
SETD2 Loss and ATR Inhibition Synergize to Promote cGAS Signaling and Immunotherapy Response in Renal Cell Carcinoma.
Liu XD et al.·Clin Cancer Res
2023
Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma.
Cotta BH et al.·Eur Urol
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and attenuate cell senescence.
Xu Y et al.·Cell Death Dis
2026
Targeting SETD2 in Cancer therapy: Structure, biological functions, and inhibitor development.
Wang P et al.·Bioorg Chem
2026
The SETD2 L1609P mutation found in leukemia disrupts methyltransferase activity and reduces histone H3K36 trimethylation.
Michail C et al.·J Biol Chem
2026🔓 Open Access
The fall of the genome protectors triad: PBRM1, SETD2, and BAP1's impact on metabolism and immunity in clear cell renal cell carcinoma.
Johnson M et al.·Front Cell Dev Biol
2025🔓 Open Access
SETD2 inhibited T-cell acute lymphocytic leukemia invasion and infiltration by inhibiting the JAK/STAT pathway.
Qiu L et al.·Mol Cell Biochem
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools