SETD1A

Chr 16AD

SET domain containing 1A, histone lysine methyltransferase

Also known as: EPEDD, EPEO2, KMT2F, NEDSID, Set1, Set1A

This protein is a histone methyltransferase that catalyzes mono-, di-, and trimethylation of histone H3 at lysine 4, a chromatin modification that marks transcription start sites of active genes. Loss-of-function mutations cause autosomal dominant early-onset epilepsy with or without developmental delay, and neurodevelopmental disorder with speech impairment and dysmorphic facies. The pathogenic mechanism involves haploinsufficiency disrupting normal gene transcription regulation.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.142 OMIM phenotypes
Clinical SummarySETD1A
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.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.14LOEUF
pLI 1.000
Z-score 7.15
OE 0.06 (0.030.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
1.83Z-score
OE missense 0.84 (0.800.89)
922 obs / 1092.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.06 (0.030.14)
00.351.4
Missense OE0.84 (0.800.89)
00.61.4
Synonymous OE1.25
01.21.6
LoF obs/exp: 4 / 67.2Missense obs/exp: 922 / 1092.3Syn Z: -4.19
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongSETD1A-related intellectual disabilityLOFAD
DN
0.19100th %ile
GOF
0.2796th %ile
LOF
0.83top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.14

Literature Evidence

LOFCharacterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.PMID:32346159

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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SETD1A · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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