MLLT3

Chr 9

MLLT3 super elongation complex subunit

Also known as: AF9, YEATS3

NCBI Gene: 4300ENSG00000171843UniProt: P42568

Enables chromatin binding activity; lysine-acetylated histone binding activity; and molecular adaptor activity. Involved in several processes, including hematopoietic stem cell differentiation; positive regulation of DNA-templated transcription; and regulation of stem cell division. Acts upstream of or within negative regulation of canonical Wnt signaling pathway and positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in cytosol and nucleoplasm. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2025]

167
ClinVar variants
76
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— MLLT3
⚡
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
76 Pathogenic / Likely Pathogenic· 64 VUS of 167 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.
0.13LOEUF
pLI 1.000
Z-score 4.42
OE 0.00 (0.00–0.13)
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.
1.90Z-score
OE missense 0.69 (0.61–0.78)
205 obs / 296.9 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.0.00 (0.00–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.61–0.78)
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.1.32
0≤1.21.6
LoF obs/exp: 0 / 22.7Missense obs/exp: 205 / 296.9Syn Z: -2.57

ClinVar Variant Classifications

167 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic5
VUS64
Likely Benign10
Benign1
71
Pathogenic
5
Likely Pathogenic
64
VUS
10
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
71
0
71
Likely Pathogenic
0
0
5
0
5
VUS
0
55
9
0
64
Likely Benign
0
0
5
5
10
Benign
0
0
0
1
1
Total055906151

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

View in ClinVar →

Protein Context — Lollipop Plot

MLLT3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mapping human haematopoietic stem cells from haemogenic endothelium to birth.
Calvanese V et al.·Nature
2022
Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions.
Perner F et al.·Int J Cancer
2026Review
The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer.
Kabra A et al.·J Mol Biol
2022Review
MLL-Rearranged Acute Lymphoblastic Leukemia.
El Chaer F et al.·Curr Hematol Malig Rep
2020Review
Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer.
Guan S et al.·Clin Cancer Res
2024Cohort
Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes.
Casado P et al.·Signal Transduct Target Ther
2023
The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.
Jankovic M et al.·Blood Adv
2024
HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia.
Arza-Apalategi S et al.·Leukemia
2025
Comprehensive molecular understanding of pediatric acute myeloid leukemia.
Shiba N·Int J Hematol
2023Review
Establishment of a high-risk pediatric AML-derived cell line YCU-AML2 with genetic and metabolic vulnerabilities.
Ikeda J et al.·Int J Hematol
2025
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
AML, ChildhoodAcute Myeloid Leukemia

Clinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML

RECRUITING
NCT06221683Phase PHASE2Children's Hospital of Soochow UniversityStarted 2024-01-01
HomoharringtonineCytarabineEtoposide
Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2AFibroblast Growth Factor Basic Form MeasurementFLT3 Internal Tandem Duplication

Nintedanib and Azacitidine in Treating Participants With HOX Gene Overexpression Relapsed or Refractory Acute Myeloid Leukemia

ACTIVE NOT RECRUITING
NCT03513484Phase PHASE1Northwestern UniversityStarted 2018-11-14
AzacitidineLaboratory Biomarker AnalysisNintedanib

External Resources

Links to major genomics databases and tools