KITLG

Summary

KITLG (KIT ligand, HGNC:6343) is a protein-coding gene on chromosome 12q21.32, encoding Kit ligand (P21583). Ligand for the receptor-type protein-tyrosine kinase KIT.

This gene encodes the ligand of the tyrosine-kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development, and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4254 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 69 (Strong, GenCC) — +8 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 151 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• MANE Select transcript: NM_000899

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6343
Approved symbol	KITLG
Name	KIT ligand
Location	12q21.32
Locus type	gene with protein product
Status	Approved
Aliases	SCF, SF, Kitl, KL-1, FPH2, SLF, DFNA69
Ensembl gene	ENSG00000049130
Ensembl biotype	protein_coding
OMIM	184745
Entrez	4254

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000347404, ENST00000357116, ENST00000378535, ENST00000552044, ENST00000644744, ENST00000646633, ENST00000874529, ENST00000874530, ENST00000874531, ENST00000944532

RefSeq mRNA: 2 — MANE Select: NM_000899 NM_000899, NM_003994

CCDS: CCDS31867, CCDS31868

Canonical transcript exons

ENST00000644744 — 10 exons

Exon	Start	End
ENSE00002335991	88492793	88497181
ENSE00003505227	88505159	88505235
ENSE00003510598	88545752	88545865
ENSE00003529612	88532441	88532503
ENSE00003560533	88518697	88518867
ENSE00003605755	88516334	88516490
ENSE00003640261	88507028	88507137
ENSE00003653872	88515534	88515617
ENSE00003681035	88506311	88506378
ENSE00003817533	88580264	88580471

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6386 / max 1375.6477, expressed in 1578 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132411	25.5371	1577
132408	0.0865	24
132409	0.0150	1

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	97.92	gold quality
cardia of stomach	UBERON:0001162	97.86	gold quality
lower lobe of lung	UBERON:0008949	97.41	gold quality
pylorus	UBERON:0001166	97.14	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.63	gold quality
middle temporal gyrus	UBERON:0002771	96.30	gold quality
parietal pleura	UBERON:0002400	95.70	gold quality
endothelial cell	CL:0000115	95.65	gold quality
skin of hip	UBERON:0001554	94.98	gold quality
pleura	UBERON:0000977	94.68	gold quality
seminal vesicle	UBERON:0000998	94.33	gold quality
renal medulla	UBERON:0000362	94.32	gold quality
vena cava	UBERON:0004087	94.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.90	gold quality
urethra	UBERON:0000057	93.86	gold quality
cauda epididymis	UBERON:0004360	93.74	gold quality
colonic mucosa	UBERON:0000317	93.52	gold quality
synovial joint	UBERON:0002217	93.16	gold quality
upper leg skin	UBERON:0004262	93.02	gold quality
mammalian vulva	UBERON:0000997	92.82	gold quality
gingiva	UBERON:0001828	92.71	gold quality
calcaneal tendon	UBERON:0003701	92.55	gold quality
gingival epithelium	UBERON:0001949	92.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.34	gold quality
mammary duct	UBERON:0001765	91.80	gold quality
colonic epithelium	UBERON:0000397	91.03	gold quality
pharyngeal mucosa	UBERON:0000355	90.88	gold quality
epithelium of nasopharynx	UBERON:0001951	90.85	gold quality
trabecular bone tissue	UBERON:0002483	90.66	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	329.08
E-CURD-119	yes	34.12
E-ANND-3	yes	14.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDH3, EZH2, FOXO1, FOXO3, HIF1A, HMGA1, JUN, MYB, NFKB, NRF1, POU3F2, RELA, STAT1, STAT5A, TAL1, TP53

miRNA regulators (miRDB)

203 targeting KITLG, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-34C-5P	99.97	70.45	1577

Literature-anchored findings (GeneRIF, showing 40)

• important factor for the growth and activation of nasal epithelial mast cells (PMID:11905054)
• Antiapoptotic cytokine IL-3 + SCF + FLT3L influence on proliferation of gamma-irradiated AC133+/CD34+ progenitor cells. (PMID:12002675)
• Comparison and modulation of angiogenic responses by FGFs, VEGF and SCF in murine and human fibrosarcomas. (PMID:12062186)
• There was a powerful and statistically significant synergy for release of IL-8, both at the mRNA level and protein level between adenosine A(2b) receptor agonists and stem cell factor (SCF). (PMID:12123753)
• SCF mRNA is present in K562, HL-60 and CML cells in blast phase (PMID:12297464)
• stem cell factor has “late” effects on fetal hemoglobin modulation during erythropoiesis, related to the expression pattern of CD117. (PMID:12393703)
• the SCF-c-kit system, possibly with the contribution of mast cells, may have a growth-regulating role in the normal pancreas, which is altered during malignant transformation. (PMID:12429808)
• several inflammatory cytokines (T helper 1 and 2) and vasoactive intestinal peptide from mast cells and nerve endings are capable of inducing stem cell factor production from epidermal keratinocytes in atopic dermatitis. (PMID:12445210)
• constitutively activated Bcr-Abl kinase pathways in primitive CML progenitors cooperate with growth factors producing a growth response, and, disrupt the normally required synergistic interactions between KL and other cytokines to achieve activation (PMID:12556557)
• SCF up-regulates Bcl-2 and Bcl-X L in erythroid precursors and exogenous expression of these proteins protects erythroblasts from caspase activation and death induced by chemotherapeutic agents. (PMID:12637332)
• SCF correlated negatively with creatinine clearance & positively with glomerular & interstitial CD68+ cells & collagen III. SCF was shown in the vicinity of alpha-SMA+ cells. This shows potential involvement of SCF/c-kit in crescentic glomerulonephritis. (PMID:12666065)
• Kit-ligand has a role in melanocyte development and epidermal homeostasis [review] (PMID:12753403)
• protein CBP/p300 was shown to be essential for EPO- and SCF-mediated STAT5 transactivation (PMID:12829027)
• long-term exposure of primitive human hematopoietic cells to elevated levels of human IL-3, GM-CSF and SF in vivo may deleteriously affect the stem cell compartment, while expanding terminal myelopoiesis. (PMID:14628073)
• findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation. (PMID:14654075)
• “Stem cell factor (SCF) also termed Kit ligand, steel factor or mast cell growth factor is the ligand of the c-kit proto-oncogene product.” P. 75 (PMID:14662725)
• Gastrointestinal stromal tumors carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course (PMID:14691917)
• SCF dose-dependently promoted survival, migration, and capillary tube formation of HUVEC cells. Akt and Erk1/2 should promote survival and capillary tube formation of these endothelial cells at a locus downstream to stem cell factor/c-kit signaling (PMID:14985355)
• the accentuated expression of SCF in lesional skin plays an important role in the mechanism involved in the epidermal hyperpigmentation of lentigo senilis (PMID:15140230)
• acquisition of autonomous growth during uveal melanoma progression may involve the SCF/c-Kit axis (PMID:15145934)
• only Kit ligand stimulated phosphorylation of signal transducer and activator of transcription 5 (PMID:15217825)
• c-Kit makes both kinase-independent and -dependent contributions to the proliferative synergy induced by SCF in combination with GM-CSF (PMID:15308671)
• induction of Slug by autocrine production of SCF and c-Kit activation plays a key role in chemoresistance of malignant mesothelioma (PMID:15337769)
• Increased stem cell factor levels are associated with tumorigenesis in neurofibromatosis type 1 (PMID:15355893)
• HMGA1 positively regulates the human KL promoter in breast and ovarian cancer cells (PMID:15378028)
• The expression of SCF and its receptor in ovarian tissue from fetuses and women suggests a possible role of SCF in growth initiation of human primordial follicles. (PMID:15474101)
• C-terminal valine defines a specific endoplasmic reticulum export signal in Kitl (PMID:15475566)
• When SCF was added with TNF-alpha, cell growth inhibition was reduced and the apoptotic cells decreased. The activations of caspase 3 and caspase 8 were almost completely blocked by SCF while CDK6 and the FLICE-inhibitory protein (FLIP) were increased. (PMID:15504546)
• HGF maintains the hematopoietic microenvironment through stimulating proliferation and adhesion to the extracellular matrix and promoting hematopoiesis through inducing constitutive production of IL-11, SDF-1 alpha, and SCF by stromal cells themselves (PMID:15504551)
• stem cell factor receptor/c-Kit has a role in signal transduction [review] (PMID:15526160)
• Coculture with murine embryos enhanced the gene expression of SCF in human ovarian granulosa tumor cells and enhanced murine embryo development. (PMID:15526978)
• The SCF is a member of a group of glycoproteins called hematopoietic cytokines (HCs). (PMID:15576295)
• Serum levels of early hemopoietic cytokine stem cell factor (SCF) correlate with disease activity in Langerhans cell histiocytosis and are relatively higher in patients with bone lesions. (PMID:15728521)
• The effect of THPO on HuMCs in the presence of rhSCF varies, depending on the relative concentration of each growth factor, while THPO alone or in combination with rhSCF supports a unique population of CD117low/CD110+ HuMCs. (PMID:15781331)
• The SCF gene was cloned into baculovirus transfer vector pVL1392 under the control of polyhedrin promoter and expressed in the Sf9 cells (Spodoptera frugiperda). (PMID:15866728)
• KIT expression is a hallmark of oncocytoma and chromophobe renal cell carcinoma. (PMID:16015044)
• Neuroprotective role for SCF in cortical neurons, an effect mediated by Akt and ERK, as well as NFkappaB-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease. (PMID:16181409)
• SCF/c-Kit interactions are likely to be involved in mediating islet cell differentiation and proliferation during human fetal pancreatic development, and that phosphorylated Akt may have a role downstream of SCF/c-Kit signaling. (PMID:16213778)
• Stem cell factor is an important cytokine in neurofibromatosis type 1 skin, but that additional (growth) factors and/or genetic mechanisms are needed to induce NF1-specific CALM hyperpigmentation. (PMID:16479403)
• SCF/c-Kit pathway plays an important role in tumor- and normal host cell-induced angiogenesis within the brain (PMID:16616334)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kitlgb	ENSDARG00000058042
danio_rerio	kitlga	ENSDARG00000070917
mus_musculus	Kitl	ENSMUSG00000019966
rattus_norvegicus	Kitlg	ENSRNOG00000005386

Protein

Protein identifiers

Kit ligand — P21583 (reviewed: P21583)

Alternative names: Mast cell growth factor, Stem cell factor, c-Kit ligand

All UniProt accessions (4): A0A2R8Y515, P21583, S4R384, S4R442

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for the receptor-type protein-tyrosine kinase KIT. Plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins.

Subunit / interactions. Homodimer, non-covalently linked. Heterotetramer with KIT, binding two KIT molecules; thereby mediates KIT dimerization and subsequent activation by autophosphorylation.

Subcellular location. Cell membrane Cytoplasm. Cytoplasm. Cytoskeleton. Cell membrane. Cell projection. Lamellipodium. Filopodium Secreted.

Post-translational modifications. A soluble form (sKITLG) is produced by proteolytic processing of isoform 1 in the extracellular domain. Found in two differentially glycosylated forms, LMW-SCF and HMW-SCF. LMW-SCF is fully N-glycosylated at Asn-145, partially N-glycosylated at Asn-90, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97 or Asn-118. HMW-SCF is N-glycosylated at Asn-118, Asn-90 and Asn-145, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97. A soluble form exists as a cleavage product of the extracellular domain.

Disease relevance. Hyperpigmentation with or without hypopigmentation, familial progressive (FPHH) [MIM:145250] A disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. Hyperpigmentation has variable intensity, and sometimes is associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. The disease is caused by variants affecting the gene represented in this entry. Deafness, congenital, unilateral or asymmetric (DCUA) [MIM:616697] An autosomal dominant form of non-syndromic, sensorineural deafness characterized by inability to hear affecting one ear. Some patients suffers from asymmetric, bilateral hearing loss. The disease is caused by variants affecting the gene represented in this entry. Waardenburg syndrome 2F (WS2F) [MIM:619947] A form of Waardenburg syndrome, an auditory-pigmentary disorder characterized by sensorineural deafness, pigmentary disturbances of the hair, skin and eyes, and absence of dystopia canthorum which is the lateral displacement of the inner canthus of each eye. WS2F is an autosomal recessive form with variable expressivity, characterized by congenital or neonatal-onset sensorineural hearing loss. The disease may be caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variants in KITLG define the skin/hair/eye pigmentation variation locus 7 (SHEP7) [MIM:611664]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair. A non-coding SNP (dbSNP:rs12821256) has been shown to be associated with classic blond hair color in Europeans. This SNP is located 350 kb upstream from KITLG, in an enhancer specifically active in the hair follicle environment. It alters a LEF1 binding site, reducing LEF1 responsiveness in cultured keratinocytes. This SNP is not associated with eye pigmentation. It is most prevalent in Northern Europe.

Similarity. Belongs to the SCF family.

Isoforms (3)

UniProt ID	Names	Canonical?
P21583-1	1, SCF248	yes
P21583-2	2, SCF220
P21583-3	3

RefSeq proteins (2): NP_000890, NP_003985 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003452	SCF	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF02404

UniProt features (44 total): sequence variant 9, glycosylation site 7, helix 5, strand 5, splice variant 3, sequence conflict 3, turn 3, chain 2, disulfide bond 2, topological domain 2, signal peptide 1, transmembrane region 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1SCF	X-RAY DIFFRACTION	2.2
1EXZ	X-RAY DIFFRACTION	2.3
8DFP	ELECTRON MICROSCOPY	3.17
8DFM	ELECTRON MICROSCOPY	3.45
2E9W	X-RAY DIFFRACTION	3.5
8DFQ	ELECTRON MICROSCOPY	3.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21583-F1	72.51	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 97 (not glycosylated)

Disulfide bonds (2): 29–114, 68–163

Glycosylation sites (7): 167, 168, 180, 195, 90, 118, 145

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1433559	Regulation of KIT signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 369 (showing top): FXR_IR1_Q6, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_EMBRYONIC_HEMOPOIESIS, BROWNE_HCMV_INFECTION_8HR_UP, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GCAAGGA_MIR502, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOMF_GROWTH_FACTOR_ACTIVITY, AAAYRNCTG_UNKNOWN, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_PIGMENTATION, RODRIGUES_NTN1_TARGETS_UP

GO Biological Process (31): ovarian follicle development (GO:0001541), neural crest cell migration (GO:0001755), hematopoietic progenitor cell differentiation (GO:0002244), myeloid leukocyte differentiation (GO:0002573), positive regulation of leukocyte migration (GO:0002687), positive regulation of myeloid leukocyte differentiation (GO:0002763), cell adhesion (GO:0007155), Ras protein signal transduction (GO:0007265), positive regulation of cell population proliferation (GO:0008284), male gonad development (GO:0008584), mast cell apoptotic process (GO:0033024), negative regulation of mast cell apoptotic process (GO:0033026), embryonic hemopoiesis (GO:0035162), ectopic germ cell programmed cell death (GO:0035234), T cell proliferation (GO:0042098), positive regulation of T cell proliferation (GO:0042102), positive regulation of melanocyte differentiation (GO:0045636), positive regulation of Ras protein signal transduction (GO:0046579), mast cell proliferation (GO:0070662), positive regulation of mast cell proliferation (GO:0070668), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), melanocyte migration (GO:0097324), mast cell migration (GO:0097531), positive regulation of hematopoietic progenitor cell differentiation (GO:1901534), positive regulation of hematopoietic stem cell proliferation (GO:1902035), developmental process involved in reproduction (GO:0003006), apoptotic process (GO:0006915), signal transduction (GO:0007165), cell population proliferation (GO:0008283), negative regulation of apoptotic process (GO:0043066), animal organ development (GO:0048513)

GO Molecular Function (4): cytokine activity (GO:0005125), stem cell factor receptor binding (GO:0005173), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), lamellipodium (GO:0030027), filopodium (GO:0030175), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by SCF-KIT	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
hemopoiesis	2
receptor ligand activity	2
female gonad development	1
anatomical structure development	1
neural crest cell development	1
mesenchymal cell migration	1
cell differentiation	1
leukocyte differentiation	1
myeloid cell differentiation	1
positive regulation of immune system process	1
regulation of leukocyte migration	1
positive regulation of cell migration	1
leukocyte migration	1
myeloid leukocyte differentiation	1
regulation of myeloid leukocyte differentiation	1
positive regulation of myeloid cell differentiation	1
positive regulation of leukocyte differentiation	1
cellular process	1
small GTPase-mediated signal transduction	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gonad development	1
development of primary male sexual characteristics	1
mast cell homeostasis	1
myeloid cell apoptotic process	1
leukocyte apoptotic process	1
negative regulation of immune system process	1
mast cell apoptotic process	1
regulation of mast cell apoptotic process	1
negative regulation of myeloid cell apoptotic process	1
negative regulation of leukocyte apoptotic process	1
embryonic organ development	1
developmental process involved in reproduction	1
programmed cell death involved in cell development	1
T cell activation	1
lymphocyte proliferation	1
T cell proliferation	1
regulation of T cell proliferation	1

Protein interactions and networks

STRING

3034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KITLG	KIT	P10721	999
KITLG	IL3	P08700	996
KITLG	NTRK1	P04629	996
KITLG	THPO	P40225	974
KITLG	FLT3LG	P49771	972
KITLG	CXCR4	P30991	960
KITLG	FLT3	P36888	953
KITLG	CD34	P28906	934
KITLG	IL6	P05231	921
KITLG	EDNRB	P24530	882
KITLG	CSF3	P09919	876
KITLG	IL7	P13232	866
KITLG	MPL	P40238	857
KITLG	CSF2	P04141	852
KITLG	CSF1R	P07333	847

IntAct

14 interactions, top by confidence:

A	B	Type	Score
KIT	KITLG	psi-mi:“MI:0407”(direct interaction)	0.540
KITLG	KIT	psi-mi:“MI:0915”(physical association)	0.540
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
KITLG	KITLG	psi-mi:“MI:0407”(direct interaction)	0.440
KITLG	PDIA3	psi-mi:“MI:0915”(physical association)	0.400
KITLG	ATP8B2	psi-mi:“MI:0914”(association)	0.350
NTNG1	UBA6	psi-mi:“MI:0914”(association)	0.350
CAMK1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
AQP3	UBXN8	psi-mi:“MI:0914”(association)	0.350
ACOT6	SPTB	psi-mi:“MI:0914”(association)	0.350
RPL35A	KITLG	psi-mi:“MI:0914”(association)	0.350
KITLG	FLT3LG	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (27): ATP8B2 (Affinity Capture-MS), PIGU (Affinity Capture-MS), KLHDC10 (Affinity Capture-MS), FLT3LG (Co-localization), KLHDC10 (Affinity Capture-MS), ATP8B2 (Affinity Capture-MS), SLC22A18 (Affinity Capture-MS), KITLG (Reconstituted Complex), PDIA3 (Proximity Label-MS), KITLG (Co-purification), KITLG (Affinity Capture-Western), KITLG (Reconstituted Complex), KLHDC10 (Affinity Capture-MS), KITLG (Co-crystal Structure), ATP13A1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QHQ6, A0A8M9PDM1, A6PWV3, A6QL94, D3Z690, F5HC71, O02699, O12980, O77515, P04401, P05402, P0DJF3, P0DP43, P12401, P17150, P18917, P19159, P20826, P21583, P21702, P33579, P33580, P46685, P52173, P79169, Q08125, Q14512, Q28586, Q29030, Q4R6V5, Q5VZ72, Q60440, Q62575, Q6AY06, Q6P7N7, Q920I0, Q95J76, Q95MD2, Q95N18, Q9CQ58

Diamond homologs: P20826, P21581, P21583, P79169, P79368, Q06220, Q09108, Q28132, Q29030, Q90314, Q95M19, Q95MD2, Q95N18

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KITLG	up-regulates	KIT	binding
HMGA1	“up-regulates quantity by expression”	KITLG	“transcriptional regulation”
KITLG	“up-regulates activity”	KIT	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

151 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	71
Likely benign	35
Benign	18

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
12813	NM_000899.5(KITLG):c.107A>G (p.Asn36Ser)	Pathogenic
1693554	NM_000899.5(KITLG):c.94C>T (p.Arg32Cys)	Pathogenic
1693555	NM_000899.5(KITLG):c.443T>C (p.Ile148Thr)	Pathogenic
1693556	NM_000899.5(KITLG):c.550_551del (p.Met184fs)	Pathogenic
1710166	NM_000899.5(KITLG):c.108T>G (p.Asn36Lys)	Pathogenic
183168	NM_000899.5(KITLG):c.98T>C (p.Val33Ala)	Pathogenic
183169	NM_000899.5(KITLG):c.100A>C (p.Thr34Pro)	Pathogenic
379240	NM_000899.5(KITLG):c.108T>A (p.Asn36Lys)	Pathogenic
1803991	NM_000899.5(KITLG):c.106A>C (p.Asn36His)	Likely pathogenic
2584392	NM_000899.5(KITLG):c.16-2A>G	Likely pathogenic
4278563	NM_000899.5(KITLG):c.101C>A (p.Thr34Asn)	Likely pathogenic

SpliceAI

1630 predictions. Top by Δscore:

Variant	Effect	Δscore
12:88505232:CATA:C	acceptor_gain	1.0000
12:88505234:TA:T	acceptor_gain	1.0000
12:88505236:C:CC	acceptor_gain	1.0000
12:88506315:T:C	donor_gain	1.0000
12:88507023:CTTA:C	donor_loss	1.0000
12:88507024:TTAC:T	donor_loss	1.0000
12:88507025:TACC:T	donor_loss	1.0000
12:88507026:A:C	donor_loss	1.0000
12:88507027:C:CT	donor_loss	1.0000
12:88507136:CC:C	acceptor_gain	1.0000
12:88507137:CC:C	acceptor_gain	1.0000
12:88516329:CTTA:C	donor_loss	1.0000
12:88516330:TTA:T	donor_loss	1.0000
12:88516332:ACCTT:A	donor_loss	1.0000
12:88516333:CCTTT:C	donor_gain	1.0000
12:88516487:GATC:G	acceptor_gain	1.0000
12:88516489:TC:T	acceptor_gain	1.0000
12:88516489:TCCTA:T	acceptor_loss	1.0000
12:88516490:CC:C	acceptor_gain	1.0000
12:88516491:C:CC	acceptor_gain	1.0000
12:88516492:T:C	acceptor_loss	1.0000
12:88518693:TTAC:T	donor_loss	1.0000
12:88518694:TA:T	donor_loss	1.0000
12:88518695:A:AT	donor_loss	1.0000
12:88518696:C:A	donor_loss	1.0000
12:88518863:CTTGG:C	acceptor_gain	1.0000
12:88518864:TTGG:T	acceptor_gain	1.0000
12:88518865:TGG:T	acceptor_gain	1.0000
12:88518866:GG:G	acceptor_gain	1.0000
12:88518867:GC:G	acceptor_loss	1.0000

AlphaMissense

1837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:88532493:A:G	L47P	0.998
12:88545753:A:G	L43S	0.998
12:88518809:A:G	L84P	0.997
12:88518853:C:A	W69C	0.997
12:88518853:C:G	W69C	0.997
12:88518796:A:C	F88L	0.996
12:88518796:A:T	F88L	0.996
12:88518798:A:G	F88L	0.996
12:88518749:A:G	L104P	0.995
12:88518818:A:G	L81S	0.995
12:88518855:A:G	W69R	0.995
12:88518855:A:T	W69R	0.995
12:88532493:A:T	L47H	0.995
12:88516434:G:C	F140L	0.994
12:88516434:G:T	F140L	0.994
12:88516436:A:G	F140L	0.994
12:88518769:A:C	N97K	0.994
12:88518769:A:T	N97K	0.994
12:88518818:A:C	L81W	0.994
12:88518857:C:G	C68S	0.994
12:88518858:A:T	C68S	0.994
12:88545753:A:C	L43W	0.994
12:88518797:A:C	F88C	0.993
12:88518797:A:G	F88S	0.993
12:88518858:A:G	C68R	0.993
12:88532491:G:T	P48T	0.993
12:88516431:A:C	F141L	0.992
12:88516431:A:T	F141L	0.992
12:88516433:A:G	F141L	0.992
12:88518856:A:C	C68W	0.992

dbSNP variants (sampled 300 via entrez): RS1000048763 (12:88567127 A>G), RS1000062491 (12:88531324 A>G), RS1000063266 (12:88578133 G>T), RS1000075123 (12:88519948 A>G,T), RS1000099091 (12:88581671 G>C), RS1000256652 (12:88493047 A>G), RS1000275363 (12:88514431 A>G), RS1000277124 (12:88510745 C>A,T), RS1000302295 (12:88581205 A>G), RS1000323417 (12:88555951 C>T), RS1000361899 (12:88500020 C>T), RS1000369625 (12:88524774 T>C,G), RS1000372032 (12:88500261 C>G), RS1000414189 (12:88518583 T>C), RS1000483578 (12:88507611 A>G)

Disease associations

OMIM: gene MIM:184745 | disease phenotypes: MIM:145250, MIM:619947, MIM:616697

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 69	Strong	Autosomal dominant
Waardenburg syndrome	Strong	Autosomal dominant
hyperpigmentation with or without hypopigmentation, familial progressive	Moderate	Autosomal dominant
familial progressive hyper- and hypopigmentation	Supportive	Autosomal dominant
familial progressive hyperpigmentation	Supportive	Autosomal dominant
Waardenburg syndrome type 2	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
Waardenburg syndrome 2F	Limited	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (9): hyperpigmentation with or without hypopigmentation, familial progressive (MONDO:0007771), Waardenburg syndrome 2F (MONDO:0030983), autosomal dominant nonsyndromic hearing loss 69 (MONDO:0014738), nonsyndromic genetic hearing loss (MONDO:0019497), familial progressive hyper- and hypopigmentation (MONDO:0017239), familial progressive hyperpigmentation (MONDO:0013648), Waardenburg syndrome type 2 (MONDO:0019517), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), Waardenburg syndrome (MONDO:0018094)

Orphanet (3): Familial progressive hyper- and hypopigmentation (Orphanet:280628), Familial progressive hyperpigmentation (Orphanet:79146), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000635	Blue irides
HP:0000957	Cafe-au-lait spot
HP:0000962	Hyperkeratosis
HP:0001003	Multiple lentigines
HP:0001010	Hypopigmentation of the skin
HP:0001034	Hypermelanotic macule
HP:0001045	Vitiligo
HP:0001053	Hypopigmented skin patches
HP:0001100	Heterochromia iridis
HP:0002211	White forelock
HP:0002216	Premature graying of hair
HP:0002251	Aganglionic megacolon
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0004414	Abnormality of the pulmonary artery
HP:0005599	Hypopigmentation of hair
HP:0007505	Progressive hyperpigmentation
HP:0008527	Congenital sensorineural hearing impairment
HP:0011364	White hair

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000118_4	Blond vs. brown hair color	4.000000e-30
GCST000414_1	Testicular germ cell tumor	1.000000e-31
GCST000414_5	Testicular germ cell tumor	3.000000e-30
GCST000416_1	Testicular cancer	6.000000e-15
GCST000701_2	Testicular germ cell cancer	2.000000e-26
GCST001765_11	Red blood cell traits	6.000000e-11
GCST001932_3	Hair color	7.000000e-19
GCST002022_11	Testicular germ cell tumor	2.000000e-50
GCST002023_10	Testicular germ cell tumor	3.000000e-13
GCST003021_4	Brown vs. non-brown hair color	1.000000e-09
GCST003022_4	Light vs. dark hair color	1.000000e-10
GCST003023_3	Blond vs non-blond hair color	1.000000e-10
GCST004635_26	Testicular germ cell tumor	3.000000e-129
GCST004713_30	Testicular germ cell tumor	1.000000e-76
GCST006075_15	Hair color	1.000000e-100
GCST006988_143	Blond vs. brown/black hair color	1.000000e-08
GCST006988_177	Blond vs. brown/black hair color	2.000000e-308
GCST006988_38	Blond vs. brown/black hair color	2.000000e-11
GCST006988_46	Blond vs. brown/black hair color	2.000000e-24
GCST006989_37	Brown vs. black hair color	1.000000e-62
GCST007504_8	Nevus count	8.000000e-09
GCST011011_21	Youthful appearance (self-reported)	7.000000e-11
GCST90002392_390	Mean corpuscular volume	5.000000e-09
GCST90011899_55	Aspartate aminotransferase levels	1.000000e-08
GCST90020054_2	Facial skin colour (CIELAB index L* value)	1.000000e-20
GCST90020056_3	Facial skin colour (CIELAB index b* value)	1.000000e-23

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0004305	erythrocyte count
EFO:0004632	nevus count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D014849	Waardenburg Syndrome	C16.131.077.938
C580334	Nonsyndromic Deafness (supp.)
C536463	Waardenburg syndrome type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2346489 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

1 measured of 4 human assays (4 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
cid_5287845	EC50	30000 nM

CTD chemical–gene interactions

138 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	7
Arsenic Trioxide	decreases expression, increases expression, decreases response to substance	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
bisphenol A	affects cotreatment, decreases methylation, decreases expression	3
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	3
Estradiol	decreases expression, increases expression	3
Aflatoxin B1	affects expression, increases expression	3
deoxynivalenol	increases expression	2
perfluorooctanoic acid	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
nutlin 3	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	affects cotreatment, increases expression	2
Gemcitabine	affects cotreatment, affects expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Doxorubicin	affects expression, increases expression	2
Lipopolysaccharides	affects cotreatment, increases secretion, increases expression	2
Methotrexate	increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases secretion	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
3,19-(2-bromobenzylidene)andrographolide	decreases expression, decreases response to substance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2349819	Binding	Inhibition of c-Kit (unknown origin) using [gamma-33P]ATP assessed as residual activity at 3 uM	Discovery and characterization of novel allosteric FAK inhibitors. — Eur J Med Chem

Cellosaurus cell lines

11 cell lines: 5 cancer cell line, 3 embryonic stem cell, 2 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_6526	Sl/Sl4 hSCF220	Transformed cell line	Sex unspecified
CVCL_6527	Sl/Sl4 hSCF248	Transformed cell line	Sex unspecified
CVCL_A3M8	SEES3-1V human KITLG, clone1	Embryonic stem cell	Male
CVCL_A3M9	SEES3-1V human KITLG, clone2	Embryonic stem cell	Male
CVCL_A3N0	SEES3-1V human KITLG, clone3	Embryonic stem cell	Male
CVCL_A9KZ	CHO Hu 164 SCF 17	Spontaneously immortalized cell line	Female
CVCL_B8JB	Abcam HCT 116 KITLG KO	Cancer cell line	Male
CVCL_B9LL	Abcam A-549 KITLG KO	Cancer cell line	Male
CVCL_D2FZ	Abcam MCF-7 KITLG KO	Cancer cell line	Female
CVCL_D7T7	Ubigene A-549 KITLG KO	Cancer cell line	Male

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT02418936	Not specified	UNKNOWN	Development and Clinical Application of Two New Genetic Deafness Gene Diagnostic Kit