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: 29072 ENSG00000181555 UniProt: Q9BYW2 OMIM: 612778

The protein functions as a histone methyltransferase that specifically methylates lysine-36 of histone H3, a modification associated with active chromatin and transcriptional regulation. Loss-of-function mutations cause autosomal dominant intellectual developmental disorders including Luscan-Lumish syndrome and Rabin-Pappas syndrome. The pathogenic mechanism involves haploinsufficiency, as evidenced by the gene's extreme intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.213 OMIM phenotypes

Clinical Summary— SETD2

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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

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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

2 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

0.21LOEUF

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 OE0.13 (0.09–0.21)

0≤0.351.4

Missense OE0.76 (0.72–0.81)

0≤0.61.4

Synonymous OE0.97

0≤1.21.6

LoF obs/exp: 14 / 106.4Missense obs/exp: 1011 / 1322.7Syn Z: 0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSETD2-related Rabin-Pappas syndromeGOFAD

strongSETD2-related overgrowth syndrome (Luscan-Lumish syndrome)LOFAD

0.2499th %ile

GOF

0.2298th %ile

LOF

0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.21

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFThese data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underPMID:29724720

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