SETD1B

Chr 12AD

SET domain containing 1B, histone lysine methyltransferase

Also known as: IDDSELD, KMT2G, Set1B

NCBI Gene: 23067 ENSG00000139718 UniProt: Q9UPS6 OMIM: 611055

SETD1B encodes a histone methyltransferase that catalyzes trimethylation of histone H3 at lysine 4 (H3K4me3), a chromatin modification essential for active gene transcription and DNA repair. Mutations cause autosomal dominant intellectual developmental disorder with seizures and language delay. The gene is highly constrained against loss-of-function variants (pLI = 1.0), reflecting its critical role in transcriptional regulation during development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).[supplied by OMIM, Mar 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— SETD1B

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

41 unique Pathogenic / Likely Pathogenic· 302 VUS of 490 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SETD1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 6.74

OE 0.07 (0.03–0.15)

Highly constrained

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

Missense Constraint?

4.67Z-score

OE missense 0.61 (0.57–0.65)

706 obs / 1151.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.15)

0≤0.351.4

Missense OE?0.61 (0.57–0.65)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 4 / 60.6Missense obs/exp: 706 / 1151.5Syn Z: -1.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSETD1B-related intellectual disability, epilepsy and autismLOFAD

This gene — mechanism propensity

0.2399th %ile

GOF

0.2696th %ile

LOF

0.83top 5%

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

LOFprediction above median · 73% of P/LP variants are LoF · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

490 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic13

VUS302

Likely Benign122

Benign12

Conflicting3

Pathogenic

Likely Pathogenic

302

VUS

122

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	5	3	0	28
Likely Pathogenic	10	3	0	0	13
VUS	3	235	64	0	302
Likely Benign	0	39	11	72	122
Benign	0	4	2	6	12
Conflicting	—				3
Total	33	286	80	78	480

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap SETD1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →