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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

72 unique Pathogenic / Likely Pathogenic· 772 VUS of 1536 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SETD2

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?

0.21LOEUF

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSETD2-related Rabin-Pappas syndromeGOFAD

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

This gene — mechanism propensity

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 · 82% of P/LP variants are LoF · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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, under1

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

References

1.PMID 29724720 ↗

ClinVar Variant Classifications

1536 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic29

VUS772

Likely Benign432

Benign108

Conflicting77

Pathogenic

Likely Pathogenic

772

VUS

432

Likely Benign

108

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	40	3	0	0	43
Likely Pathogenic	19	10	0	0	29
VUS	6	748	13	5	772
Likely Benign	0	124	73	235	432
Benign	1	45	45	17	108
Conflicting	—				77
Total	66	930	131	257	1,461

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap SETD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →