KMT2C

Chr 7AD

lysine methyltransferase 2C

Also known as: HALR, KLEFS2, MLL3

NCBI Gene: 58508ENSG00000055609UniProt: Q8NEZ4

This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Kleefstra syndrome 2MIM #617768
AD
493
ClinVar variants
17
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— KMT2C
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · 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
17 Pathogenic / Likely Pathogenic· 241 VUS of 493 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.12LOEUF
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?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.
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?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.0.08 (0.06–0.12)
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 (0.85–0.91)
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.1.02
0≤1.21.6
LoF obs/exp: 18 / 219.2Missense obs/exp: 2226 / 2528.2Syn Z: -0.53

ClinVar Variant Classifications

493 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic6
VUS241
Likely Benign165
Benign61
Conflicting9
11
Pathogenic
6
Likely Pathogenic
241
VUS
165
Likely Benign
61
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
7
0
11
Likely Pathogenic
1
3
2
0
6
VUS
0
221
19
1
241
Likely Benign
0
65
47
53
165
Benign
0
20
5
36
61
Conflicting
—9
Total53098090493

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.

Gene2Phenotype Curations

KMT2C-related intellectual disability

strong
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 2

MIM #617768

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
KMT2C and KMT2D aberrations in breast cancer.
Tinsley E et al.·Trends Cancer
2024Review
Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.
Rots D et al.·Am J Hum Genet
2024
KMT2C deficiency drives transdifferentiation of double-negative prostate cancer and confer resistance to AR-targeted therapy.
Guo J et al.·Cancer Cell
2025
Penetrance, variable expressivity and monogenic neurodevelopmental disorders.
de Masfrand S et al.·Eur J Med Genet
2024
Identification of genomic alterations in oesophageal squamous cell cancer.
Song Y et al.·Nature
2014
Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature.
Li X et al.·J Clin Endocrinol Metab
2022
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
Faundes V et al.·Am J Hum Genet
2018
Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
Philip PA et al.·Clin Cancer Res
2022Cohort
CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.
Huang YH et al.·Signal Transduct Target Ther
2021
TAOK3 Facilitates Esophageal Squamous Cell Carcinoma Progression and Cisplatin Resistance Through Augmenting Autophagy Mediated by IRGM.
Sun M et al.·Adv Sci (Weinh)
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
KMT2C Loss Promotes NF2-Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling.
Zhang L et al.·Adv Sci (Weinh)
2026
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
2025🔓 Open 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
Kmt2c/Mll3 Haploinsufficiency Causes Autism-like Behavioral Deficits in Mice.
Ma K et al.·Biomolecules
2025🔓 Open Access
MEX3A-mediated super-enhancer RNA m6A methylation promotes aggressiveness of breast cancer via regulating RBM15B/IGF2BP3/KMT2C signaling.
Zhang Y et al.·Transl Oncol
2026🔓 Open Access
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

External Resources

Links to major genomics databases and tools