EHMT1

Chr 9AD

euchromatic histone lysine methyltransferase 1

Also known as: EHMT1-IT1, EUHMTASE1, Eu-HMTase1, FP13812, GLP, GLP1, KLEFS1, KMT1D

NCBI Gene: 79813ENSG00000181090UniProt: Q9H9B1

The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

Primary Disease Associations & Inheritance

Kleefstra syndrome 1MIM #610253
AD
280
ClinVar variants
50
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— EHMT1
🧬
Gene-Disease Validity (ClinGen)
Kleefstra syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 141 VUS of 280 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.07LOEUF
pLI 1.000
Z-score 7.42
OE 0.02 (0.00–0.07)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.16Z-score
OE missense 0.88 (0.83–0.94)
713 obs / 805.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.00–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.83–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.22
0≤1.21.6
LoF obs/exp: 1 / 66.1Missense obs/exp: 713 / 805.9Syn Z: -3.17

ClinVar Variant Classifications

280 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic11
VUS141
Likely Benign78
Benign9
Conflicting2
39
Pathogenic
11
Likely Pathogenic
141
VUS
78
Likely Benign
9
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
1
21
0
39
Likely Pathogenic
6
2
3
0
11
VUS
5
122
10
4
141
Likely Benign
0
15
34
29
78
Benign
0
4
1
4
9
Conflicting
—2
Total281446937280

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

View in ClinVar →

Protein Context — Lollipop Plot

EHMT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EHMT1-related Kleefstra syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Kleefstra syndrome 1

MIM #610253

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — EHMT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.
Rots D et al.·Am J Hum Genet
2024
Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.
Rots D et al.·Am J Hum Genet
2024Functional
EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms.
Nachiyappan A et al.·FEBS J
2022Review
BRD4 acts as a transcriptional repressor of RhoB to inhibit terminal erythropoiesis.
Chen Y et al.·J Hematol Oncol
2025
EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell-Dependent Manner.
Nguyen LL et al.·Mol Cancer Res
2024
Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome.
Ren R et al.·BMC Med Genomics
2024Cohort
A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review.
Tzetis M et al.·Genes (Basel)
2025Review
Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome.
Frazier ZJ et al.·Clin Genet
2025Cohort
Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile.
Rots D et al.·Clin Genet
2024
ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia.
Zhu L et al.·Cancer Control
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools