SETD2

Chr 3

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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtRenal cell carcinoma
UniProtLuscan-Lumish syndrome
UniProtLeukemia, acute lymphoblastic
UniProtLeukemia, acute myelogenous

Clinical highlights

Gene-disease validity (ClinGen)
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome · ADStrongappropriate for clinical testing2 gene-disease associations curated in total
Interpreting a novel variant
Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.
2
Active trials
208
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.21
LOEUF· LoF intol.
Multiple*
Mechanism· G2P
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GeneReview available — SETD2
Authoritative clinical overview · Recommended first read
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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?
0.21LOEUF
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?
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?
LoF OE?0.13 (0.09–0.21)
0≤0.351.4
Missense OE?0.76 (0.72–0.81)
0≤0.61.4
Synonymous OE?0.97
0≤1.21.6
LoF obs/exp: 14 / 106.4Missense obs/exp: 1011 / 1322.7Syn Z: 0.45

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

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