KMT2C

Chr 7AD

lysine methyltransferase 2C

Also known as: HALR, KLEFS2, MLL3

NCBI Gene: 58508ENSG00000055609UniProt: Q8NEZ4OMIM: 606833

This histone methyltransferase catalyzes H3K4 methylation and functions in chromatin remodeling and transcriptional regulation. Mutations cause Kleefstra syndrome 2, a neurodevelopmental disorder with intellectual disability, developmental delay, and dysmorphic features, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 1), consistent with its essential role in normal development.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.121 OMIM phenotype
Clinical Summary— KMT2C
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Gene-Disease Validity (ClinGen)
syndromic intellectual disability · 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
11 unique Pathogenic / Likely Pathogenic· 97 VUS of 200 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 →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.12LOEUF
pLI 1.000
Z-score 12.59
OE 0.08 (0.06–0.12)
Highly constrained

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

Missense Constraint
2.14Z-score
OE missense 0.88 (0.85–0.91)
2226 obs / 2528.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.08 (0.06–0.12)
0≤0.351.4
Missense OE0.88 (0.85–0.91)
0≤0.61.4
Synonymous OE1.02
0≤1.21.6
LoF obs/exp: 18 / 219.2Missense obs/exp: 2226 / 2528.2Syn Z: -0.53
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongKMT2C-related intellectual disabilityLOFAD
DN
0.2299th %ile
GOF
0.06100th %ile
LOF
0.84top 5%

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

LOFprediction above median · 1 literature citation · 55% of P/LP variants are LoF · LOEUF 0.12

Literature Evidence

LOFGirirajan et al. (2013) conducted a large-scale case-control study (2588 patients; 580 controls) of an autism patient cohort to identify segmental duplication mediated and associated recurrent genomic hotspots for copy number variants, and dosage sensitive genes, using custom targeted high density aPMID:23375656

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

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic4
VUS97
Likely Benign23
Benign5
7
Pathogenic
4
Likely Pathogenic
97
VUS
23
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
1
0
7
Likely Pathogenic
0
4
0
0
4
VUS
0
91
6
0
97
Likely Benign
0
6
7
10
23
Benign
0
1
0
4
5
Total61021414136

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

View in ClinVar →

Protein Context — Lollipop Plot

KMT2C · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.
Zhao Z et al.·Nat Rev Cancer
2026
Novel Variants in KMT2C Further Support a Neurodevelopmental Disorder Distinct From Kleefstra and Kabuki Syndromes.
Sedláčková L et al.·Mol Genet Genomic Med
2026
KMT2C Loss Promotes NF2-Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling.
Zhang L et al.·Adv Sci (Weinh)
2026Open Access
Identification of a chromatin-modifying gene-histone lysine N-methyl transferase (KMT2C/MLL3) as a potential immunomodulator oncogene in Indian pancreatic cancer patients.
Choudhury S et al.·Eur J Med Res
2025Open AccessCohort
KMT2C mutations in breast cancer: molecular mechanisms of cancer promotion, clinical significance, and potential as biomarkers.
Hsu MC et al.·Crit Rev Oncol Hematol
2026Functional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients