FLT3

protein-coding

fms related receptor tyrosine kinase 3, the group of Receptor tyrosine kinases|Immunoglobulin like domain containing|CD molecules

Gene summary

This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [provided by RefSeq, Jan 2015]

MANE transcript

NM_004119.3

Inheritance

ClinVar variants

P:9U:100B:44

Top phenotype

Acute myeloid leukemia

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr13:28,003,274-28,100,592

External References & Databases

Ensembl (ENSG00000122025)

Transcript & Mutation Effects

hg38 • Region Span ~97.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukemia, acute myeloid, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100173

Submitter: ClinGen

FLT3 was first reported in relation to autosomal dominant leukemia predisposition in 2016 (de Smith et al., PMID: 27683039). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found insufficient evidence of difference in molecular mechanisms, inheritance patterns, or phenotypic variability, although in the small number of reported patients the majority presented with myeloid-related disease. Therefore, the following disease entities have been lumped into one disease entity: predisposition to B-ALL, aplastic anaemia, MDS and AML. Seven missense variants that have been reported in 8 probands in 5 publications (PMIDs: 27683039, 33283233, 38212634, 39080258, 39773519) are included in this curation. The mechanism of pathogenicity is known to be gain of function. This gene-disease relationship is also supported by animal models, expression studies and in vitro functional assays (PMIDs: 7630197, 10698507, 11756186, 12796379). FLT3 is expressed in hematopoietic cells and leads to AKT and MAPK pathway activation (PMID: 7630197, 12796379). Activating alterations in FLT3 result in cell proliferation and viability, with constitutive activation of STAT and MAPK pathways (PMID: 10698507). Activating FLT3 alterations in a murine BMT model can induce myeloproliferative disease (PMID: 11756186), however an activating FLT3 alteration alone in a murine model is not sufficient to cause leukemogenesis (PMID: 25873173). In summary, there is limited evidence supporting the relationship between FLT3 and autosomal dominant leukemia predisposition. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date 18th November 2025 (SOP Version 11].

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FLT3 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 102

not providedTotal: 51

Acute myeloid leukemiaTotal: 10

FLT3-related disorderTotal: 6

Acute lymphoid leukemiaTotal: 3

Multiple myelomaTotal: 1

Myelodysplastic syndrome progressed to acute myeloid leukemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004119.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				18 clinvar	8 clinvar	26
missense	5 clinvar	4 clinvar	92 clinvar	13 clinvar	5 clinvar	119
nonsense						0
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	5	4	100	31	13	153

Highest pathogenic variant AF is 0.000029119548

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004119.3	RefSeq	NP_004110.2	24	MANE Select
ENST00000241453.12	Ensembl	ENSP00000241453.7	24	MANE Select
ENST00000380987.2	Ensembl	ENSP00000370374.2	18	Standard
ENST00000864668.1	Ensembl	ENSP00000534727.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Central carbon metabolism in cancer - Homo sapiens (human)
Acute myeloid leukemia - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)

Biological Process

MAPK cascade
leukocyte homeostasis
hematopoietic progenitor cell differentiation
myeloid progenitor cell differentiation
pro-B cell differentiation

Molecular Function

transmembrane receptor protein tyrosine kinase activity
cytokine receptor activity
vascular endothelial growth factor-activated receptor activity
Ras guanyl-nucleotide exchange factor activity
protein binding

Cellular Component

nucleus
endoplasmic reticulum
endoplasmic reticulum lumen
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000241453
Coding exons: 24
Length: 97319
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125747
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.982	461	524	0.879	0.0000267	6539
Missense (PolyPhen)		116	167.76	0.69147		2085
Synonymous	-0.0968	206	204	1.01	0.0000123	1810
Loss of Function	5.42	12	55.6	0.216	0.00000250	721

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, ECO:0000269|PubMed:7507245}.;
Disease: DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:11290608, ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:18305215, ECO:0000269|PubMed:8946930, ECO:0000269|PubMed:9737679}. Note=The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase.;

Recessive Scores

pRec: 0.351

Intolerance Scores

LoFtool: 0.218
RVIS EVS: 0.1
RVIS percentile EVS: 60.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium