SETD1A

Chr 16AD

SET domain containing 1A, histone lysine methyltransferase

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

NCBI Gene: 9739 ENSG00000099381 UniProt: O15047 OMIM: 611052

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.142 OMIM phenotypes

Clinical Summary— SETD1A

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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

71 unique Pathogenic / Likely Pathogenic· 494 VUS of 814 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 7.15

OE 0.06 (0.03–0.14)

Highly constrained

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

Missense Constraint?

1.83Z-score

OE missense 0.84 (0.80–0.89)

922 obs / 1092.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.14)

0≤0.351.4

Missense OE?0.84 (0.80–0.89)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 4 / 67.2Missense obs/exp: 922 / 1092.3Syn Z: -4.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSETD1A-related intellectual disabilityLOFAD

This gene — mechanism propensity

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 · 83% of P/LP variants are LoF · LOEUF 0.14 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFCharacterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.1

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 32346159 ↗

ClinVar Variant Classifications

814 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34

Likely Pathogenic37

VUS494

Likely Benign189

Benign10

Conflicting29

Pathogenic

Likely Pathogenic

494

VUS

189

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	3	0	0	34
Likely Pathogenic	28	8	0	1	37
VUS	12	465	15	2	494
Likely Benign	1	88	5	95	189
Benign	0	3	2	5	10
Conflicting	—				29
Total	72	567	22	103	793

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap SETD1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →