Systemic mastocytosis

Summary

Systemic mastocytosis (MONDO:0016586) is a disease (an umbrella term covering 5 Mondo subtypes) with 13 cohort genes (17 GWAS associations across 1 studies) and 28 clinical trials. Molecularly, KIT D816V confers sensitivity to Avapritinib in Systemic Mastocytosis (CIViC Level A); 7 further subtype–drug associations are mapped below. Top therapeutic interventions include imatinib, avapritinib, and brentuximab vedotin.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 13
• GWAS associations: 17
• ClinVar variants: 1
• Clinical trials: 28
• Precision-medicine evidence (CIViC): 8 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Worldwide	Validated
Annual incidence	1-9 / 1 000 000	0.6	Europe	Validated
Point prevalence	1-5 / 10 000	11.3	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.3	Italy	Validated
Annual incidence	1-9 / 1 000 000	0.9	Denmark	Validated
Point prevalence	1-9 / 100 000	9.6	Denmark	Validated
Point prevalence	1-5 / 10 000	13	Netherlands	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	systemic mastocytosis
Mondo ID	MONDO:0016586
Orphanet	2467
DOID	DOID:349
ICD-10-CM	D47.02
ICD-11	1144812971
NCIT	C9235
SNOMED CT	397016004
UMLS	C0221013
MedGen	67436
GARD	0008616
MedDRA	10042949
Is cancer (heuristic)	no

Also known as: Aggressive systemic mastocytosis · Mast cell disease · SM · systemic mast cell disease · systemic mastocytosis · systemic mastocytosis with associated hemotologic non-mast cell lineage disease (SM-AHNMD) · systemic tissue Mast cell disease · systemic tissue mast cell disease

Data availability: 1 ClinVar variant · 17 GWAS associations (1 study) · 16 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › myeloid neoplasm › mast cell neoplasm › mastocytosis › systemic mastocytosis

Related subtypes (4): cutaneous mastocytosis, mast cell sarcoma, acute mast cell leukemia, chronic mast cell leukemia

Subtypes (5): extracutaneous mastocytoma, indolent systemic mastocytosis, systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease, aggressive systemic mastocytosis, mast cell leukemia

Genetics & variants

GWAS landscape

17 GWAS associations across 1 studies. Top hits map to 14 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs10838094	7e-12	OR51B5, OR51Q1, HBG2, HBE1	A	0.28
rs2857596	2e-10	NCR3 - UQCRHP1	C	2.58
rs498404	3e-10	TTC39B - RPL7P33	G	2.7
rs1479010	1e-08	NAV3	T	2.33
rs9828758	2e-08	PRDX5P1 - LINC02005	T	0.15
rs9937881	3e-08	TPSAB1 - TPSD1	T	2.29
rs80138802	4e-08	ABCA2	C	4.1
rs45487695	5e-08	MOCS1	T	5.59
rs954009	6e-08	RANP9 - RNU6-528P	C	2.22
rs1820510	6e-08	SPMIP2	A	3.63
rs17404123	9e-08	EYS	C	2.52
exm529784	1e-07		T	2.18
rs2230808	1e-07	ABCA1	A	2.19
rs807816	4e-07	CDKAL1 - LINC00581	G	2.5
rs12402123	6e-07	CACNA1E	T	2.81
rs35701577	8e-07	MEGF6	C	2.18
rs3131382	9e-07	MSH5, CLIC1	A	3.25

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST011382	Nedoszytko B	2020	93	5,606	Results from a Genome-Wide Association Study (GWAS) in Mastocytosis Reveal New Gene Polymorphisms Associated with WHO Subgroups.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	13

MAF distribution

Bucket	Variants
common (>=0.05)	13
low_freq (0.01-0.05)	3
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intron_variant	6
intergenic_variant	5
missense_variant	3
synonymous_variant	1
unknown	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs10838094	11	5422663	G>A,C	0.411	missense_variant	OR51B5, OR51Q1, HBG2, HBE1	7e-12	Tier 1: coding
rs2857596	6	31599645	G>T	0.239	intergenic_variant	NCR3 - UQCRHP1	2e-10	Tier 4: intronic/intergenic
rs498404	9	15347024	G>A,C,T	0.137	intergenic_variant	TTC39B - RPL7P33	3e-10	Tier 4: intronic/intergenic
rs1479010	12	78014990	A>C,G,T	0.422	intron_variant	NAV3	1e-08	Tier 4: intronic/intergenic
rs9828758	3	73668985	C>G,T	0.293	intergenic_variant	PRDX5P1 - LINC02005	2e-08	Tier 4: intronic/intergenic
rs9937881	16	1247070	C>T	0.209	intergenic_variant	TPSAB1 - TPSD1	3e-08	Tier 4: intronic/intergenic
rs80138802	9	137021488	A>C,G	0.024	synonymous_variant	ABCA2	4e-08	Tier 4: intronic/intergenic
rs45487695	6	39927524	C>A,G,T	0.009	intron_variant	MOCS1	5e-08	Tier 4: intronic/intergenic
rs954009	8	33337937	T>C	0.237	intergenic_variant	RANP9 - RNU6-528P	6e-08	Tier 4: intronic/intergenic
rs1820510	4	158952044	C>A,G,T	0.029	intron_variant	SPMIP2	6e-08	Tier 4: intronic/intergenic
rs17404123	6	64593207	T>C,G	0.106	missense_variant	EYS	9e-08	Tier 1: coding
exm529784				0.249			1e-07	Tier 4: intronic/intergenic
rs2230808	9	104800523	T>A,C,G	0.247	missense_variant	ABCA1	1e-07	Tier 1: coding
rs807816	6	21263889	A>G	0.09	intron_variant	CDKAL1 - LINC00581	4e-07	Tier 4: intronic/intergenic
rs12402123	1	181520882	C>T	0.055	intron_variant	CACNA1E	6e-07	Tier 4: intronic/intergenic
rs35701577	1	3605997	T>A,C	0.173	intron_variant	MEGF6	8e-07	Tier 4: intronic/intergenic
rs3131382	6	31739953	T>A,C,G	0.032	regulatory_region_variant	MSH5, CLIC1	9e-07	Tier 3: regulatory

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
592102	NM_000222.3(KIT):c.2872A>G (p.Asn958Asp)	KIT	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIT	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
KIT	Orphanet:158766	Typical urticaria pigmentosa
KIT	Orphanet:158769	Plaque-form urticaria pigmentosa
KIT	Orphanet:158772	Nodular urticaria pigmentosa
KIT	Orphanet:158775	Smoldering systemic mastocytosis
KIT	Orphanet:158778	Isolated bone marrow mastocytosis
KIT	Orphanet:280785	Bullous diffuse cutaneous mastocytosis
KIT	Orphanet:280794	Pseudoxanthomatous diffuse cutaneous mastocytosis
KIT	Orphanet:2884	Piebaldism
KIT	Orphanet:44890	Gastrointestinal stromal tumor
KIT	Orphanet:566393	Acute mast cell leukemia
KIT	Orphanet:566396	Chronic mast cell leukemia
KIT	Orphanet:79455	Cutaneous mastocytoma
KIT	Orphanet:842	Testicular seminomatous germ cell tumor
KIT	Orphanet:90389	Telangiectasia macularis eruptiva perstans
KIT	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
KIT	Orphanet:98834	Acute myeloblastic leukemia with maturation
KIT	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
CACNA1E	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PRPF31	Orphanet:791	Retinitis pigmentosa
CDSN	Orphanet:263553	Peeling skin syndrome type B
CDSN	Orphanet:90368	Hypotrichosis simplex of the scalp
EYS	Orphanet:791	Retinitis pigmentosa
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency
ABCA2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
MOCS1	Orphanet:308386	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A
MSH5	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	12
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIT	HGNC:6342	ENSG00000157404	P10721	Mast/stem cell growth factor receptor Kit	clinvar,civic_evidence
CACNA1E	HGNC:1392	ENSG00000198216	Q15878	Voltage-dependent R-type calcium channel subunit alpha-1E	gwas
OR51Q1	HGNC:14851	ENSG00000167360	Q8NH59	Olfactory receptor 51Q1	gwas
PRPF31	HGNC:15446	ENSG00000105618	Q8WWY3	U4/U6 small nuclear ribonucleoprotein Prp31	gwas
NAV3	HGNC:15998	ENSG00000067798	Q8IVL0	Neuron navigator 3	gwas
CDSN	HGNC:1802	ENSG00000204539	Q15517	Corneodesmosin	gwas
EYS	HGNC:21555	ENSG00000188107	Q5T1H1	Protein eyes shut homolog	gwas
SPMIP2	HGNC:26342	ENSG00000164123	Q96LM5	Protein SPMIP2	gwas
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	gwas
ABCA2	HGNC:32	ENSG00000107331	Q9BZC7	ATP-binding cassette sub-family A member 2	gwas
MEGF6	HGNC:3232	ENSG00000162591	O75095	Multiple epidermal growth factor-like domains protein 6	gwas
MOCS1	HGNC:7190	ENSG00000124615	Q9NZB8	Molybdenum cofactor biosynthesis protein 1	gwas
MSH5	HGNC:7328	ENSG00000204410	O43196	MutS protein homolog 5	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIT	Mast/stem cell growth factor receptor Kit	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell develo…
CACNA1E	Voltage-dependent R-type calcium channel subunit alpha-1E	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.
OR51Q1	Olfactory receptor 51Q1	Odorant receptor.
PRPF31	U4/U6 small nuclear ribonucleoprotein Prp31	Involved in pre-mRNA splicing as component of the spliceosome.
NAV3	Neuron navigator 3	Is involved in microtubule cytoskeleton organization and plays a role in cell migration.
CDSN	Corneodesmosin	Important for the epidermal barrier integrity.
EYS	Protein eyes shut homolog	Required to maintain the integrity of photoreceptor cells.
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
ABCA2	ATP-binding cassette sub-family A member 2	Probable lipid transporter that modulates cholesterol sequestration in the late endosome/lysosome by regulating the intracellular sphingolipid metabolism, in turn participates in cholesterol homeostasis.
MOCS1	Molybdenum cofactor biosynthesis protein 1	Isoform MOCS1A and isoform MOCS1B probably form a complex that catalyzes the conversion of 5’-GTP to cyclic pyranopterin monophosphate (cPMP).
MSH5	MutS protein homolog 5	Involved in DNA mismatch repair and meiotic recombination processes.

Protein-family classification

Druggable: 6 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.46

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	2	12.0×	0.070
Ion channel	1	8.6×	0.332
Kinase	1	2.1×	0.639
GPCR	1	1.8×	0.639
Other/Unknown	7	1.0×	0.678
Enzyme (other)	1	0.9×	0.678

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIT	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
CACNA1E	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_R_a1su
OR51Q1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
PRPF31	Other/Unknown	no		Nop_dom, NOSIC, Prp31_C
NAV3	Other/Unknown	no		CH_dom, AAA+_ATPase, ATPase_AAA_core
CDSN	Other/Unknown	no		Corneodesmosin
EYS	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
SPMIP2	Other/Unknown	no		DUF4562
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
ABCA2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
MEGF6	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MOCS1	Enzyme (other)	yes	4.1.99.22	MoaA_NifB_PqqE_Fe-S-bd_CS, Mopterin_CF_biosynth-C_dom, Elp3/MiaA/NifB-like_rSAM
MSH5	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS_core, DNA_mismatch_repair_MutS_clamp

Expression context

Cohort genes with no expression data: 0.

9 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
cortical plate	2
middle temporal gyrus	2
male germ line stem cell (sensu Vertebrata) in testis	2
left testis	2
lateral nuclear group of thalamus	1
oocyte	1
secondary oocyte	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
granulocyte	1
stromal cell of endometrium	1
ventricular zone	1
skin of abdomen	1
skin of leg	1
zone of skin	1
islet of Langerhans	1
primordial germ cell in gonad	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIT	263	broad	marker	lateral nuclear group of thalamus, secondary oocyte, oocyte
CACNA1E	144	broad	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
OR51Q1	2		yes	sural nerve, colonic epithelium, calcaneal tendon
PRPF31	134	ubiquitous	marker	stromal cell of endometrium, granulocyte, ventricular zone
NAV3	232	ubiquitous	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
CDSN	101	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg
EYS	153	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans
SPMIP2	122	tissue_specific	yes	sperm, male germ line stem cell (sensu Vertebrata) in testis, left testis
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland
ABCA2	234	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum
MEGF6	205	ubiquitous	marker	right coronary artery, descending thoracic aorta, ascending aorta
MOCS1	245	ubiquitous	marker	apex of heart, popliteal artery, tibial artery
MSH5	134	ubiquitous	yes	right uterine tube, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIT	6,087
ABCA1	3,551
PRPF31	3,427
CACNA1E	2,008
EYS	1,877
ABCA2	1,678
MSH5	1,572
MOCS1	1,494
CDSN	1,223
NAV3	963

Intra-cohort edges

A	B	Sources
ABCA1	ABCA2	biogrid_interaction
ABCA2	OR51Q1	string_interaction
EYS	PRPF31	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIT	P10721	52
PRPF31	Q8WWY3	30
ABCA1	O95477	7
CACNA1E	Q15878	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR51Q1	Q8NH59	85.83
MSH5	O43196	82.36
MOCS1	Q9NZB8	79.87
ABCA2	Q9BZC7	71.46
MEGF6	O75095	70.56
SPMIP2	Q96LM5	62.74
NAV3	Q8IVL0	48.21
CDSN	Q15517	38.13
EYS	Q5T1H1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. Enrichment computed across 13 evidence-associated genes (9 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dasatinib-resistant KIT mutants	1	1268.9×	0.005	KIT
Imatinib-resistant KIT mutants	1	1268.9×	0.005	KIT
KIT mutants bind TKIs	1	1268.9×	0.005	KIT
Masitinib-resistant KIT mutants	1	1268.9×	0.005	KIT
Nilotinib-resistant KIT mutants	1	1268.9×	0.005	KIT
Regorafenib-resistant KIT mutants	1	1268.9×	0.005	KIT
Signaling by kinase domain mutants of KIT	1	1268.9×	0.005	KIT
Sunitinib-resistant KIT mutants	1	1268.9×	0.005	KIT
Signaling by juxtamembrane domain KIT mutants	1	1268.9×	0.005	KIT
Sorafenib-resistant KIT mutants	1	1268.9×	0.005	KIT
Drug resistance of KIT mutants	1	1268.9×	0.005	KIT
Signaling by extracellular domain mutants of KIT	1	1268.9×	0.005	KIT
Defective ABCA1 causes TGD	1	634.4×	0.008	ABCA1
Molybdenum cofactor biosynthesis	1	181.3×	0.027	MOCS1
HDL assembly	1	158.6×	0.029	ABCA1
Signaling by KIT in disease	1	126.9×	0.034	KIT
Presynaptic depolarization and calcium channel opening	1	105.7×	0.038	CACNA1E
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	84.6×	0.045	KIT
Plasma lipoprotein assembly	1	79.3×	0.045	ABCA1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	70.5×	0.045	KIT
Developmental Lineage of Mammary Gland Alveolar Cells	1	70.5×	0.045	KIT
ABC transporters in lipid homeostasis	1	66.8×	0.045	ABCA2
Regulation of KIT signaling	1	66.8×	0.045	KIT
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	57.7×	0.049	KIT
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	50.8×	0.054	KIT
ABC transporter disorders	1	48.8×	0.054	ABCA1
NR1H2 and NR1H3-mediated signaling	1	43.8×	0.058	ABCA1
PI3K/AKT Signaling in Cancer	1	40.9×	0.060	KIT
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	34.3×	0.069	ABCA1
Meiosis	1	31.7×	0.071	MSH5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosphingolipid metabolic process	2	437.7×	0.001	KIT, ABCA2
negative regulation of intracellular cholesterol transport	1	1532.0×	0.010	ABCA2
negative regulation of phospholipid biosynthetic process	1	1532.0×	0.010	ABCA2
ribonucleoprotein complex localization	1	1532.0×	0.010	PRPF31
negative regulation of sphingolipid biosynthetic process	1	1532.0×	0.010	ABCA2
melanocyte adhesion	1	1532.0×	0.010	KIT
positive regulation of pyloric antrum smooth muscle contraction	1	1532.0×	0.010	KIT
positive regulation of colon smooth muscle contraction	1	1532.0×	0.010	KIT
regulation of protein localization to cell periphery	1	1532.0×	0.010	ABCA2
negative regulation of cornification	1	1532.0×	0.010	CDSN
corneocyte desquamation	1	766.0×	0.011	CDSN
response to vitamin B3	1	766.0×	0.011	ABCA1
negative regulation of steroid metabolic process	1	766.0×	0.011	ABCA2
regulation of high-density lipoprotein particle assembly	1	766.0×	0.011	ABCA1
positive regulation of high-density lipoprotein particle assembly	1	766.0×	0.011	ABCA1
ceramide translocation	1	766.0×	0.011	ABCA2
regulation of post-translational protein modification	1	766.0×	0.011	ABCA2
positive regulation of vascular associated smooth muscle cell differentiation	1	766.0×	0.011	KIT
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	766.0×	0.011	ABCA2
signal release	1	510.7×	0.012	ABCA1
positive regulation of low-density lipoprotein particle receptor catabolic process	1	510.7×	0.012	ABCA2
Fc receptor signaling pathway	1	510.7×	0.012	KIT
Kit signaling pathway	1	510.7×	0.012	KIT
melanocyte migration	1	510.7×	0.012	KIT
obsolete regulation of bile acid metabolic process	1	510.7×	0.012	KIT
positive regulation of small intestine smooth muscle contraction	1	510.7×	0.012	KIT
ganglioside metabolic process	1	383.0×	0.012	ABCA2
mast cell chemotaxis	1	383.0×	0.012	KIT
peptide secretion	1	383.0×	0.012	ABCA1
regulation of intracellular cholesterol transport	1	383.0×	0.012	ABCA2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 10

Druggability breadth: 4 of 13 evidence-associated genes (31%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KIT	PONATINIB
CACNA1E	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIT	99	4
CACNA1E	2	4
PRPF31	1	2
OR51Q1	0	0
NAV3	0	0
CDSN	0	0
EYS	0	0
SPMIP2	0	0
ABCA1	0	0
ABCA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	KIT
FEDRATINIB	4	KIT
TIVOZANIB	4	KIT
LENVATINIB	4	KIT
AXITINIB	4	KIT
SORAFENIB	4	KIT
DASATINIB ANHYDROUS	4	KIT
NICLOSAMIDE	4	KIT
IMATINIB MESYLATE	4	KIT
RUXOLITINIB	4	KIT
INFIGRATINIB PHOSPHATE	4	KIT
INFIGRATINIB	4	KIT
REGORAFENIB	4	KIT
ENTRECTINIB	4	KIT
CABOZANTINIB	4	KIT
CERITINIB	4	KIT
VANDETANIB	4	KIT
NILOTINIB	4	KIT
BOSUTINIB	4	KIT
BRIGATINIB	4	KIT
PEXIDARTINIB	4	KIT
AVAPRITINIB	4	KIT
RIPRETINIB	4	KIT
PAZOPANIB	4	KIT
NINTEDANIB	4	KIT
SUNITINIB	4	KIT
DASATINIB	4	KIT
ERLOTINIB	4	KIT
QUIZARTINIB	4	KIT
CRIZOTINIB	4	KIT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KIT	2,305	Binding:2242, ADMET:32, Functional:22, Toxicity:9
CACNA1E	14	Binding:14
PRPF31	6	Binding:6
ABCA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIT	2.7.10.1	receptor protein-tyrosine kinase
MOCS1	4.1.99.22, 4.6.1.17	GTP 3’,8-cyclase, cyclic pyranopterin monophosphate synthase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KIT	2,305

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

27 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	KIT
FEDRATINIB	4	KIT
TIVOZANIB	4	KIT
LENVATINIB	4	KIT
AXITINIB	4	KIT
SORAFENIB	4	KIT
DASATINIB ANHYDROUS	4	KIT
NICLOSAMIDE	4	KIT
IMATINIB MESYLATE	4	KIT
RUXOLITINIB	4	KIT
INFIGRATINIB PHOSPHATE	4	KIT
INFIGRATINIB	4	KIT
REGORAFENIB	4	KIT
ENTRECTINIB	4	KIT
CABOZANTINIB	4	KIT
CERITINIB	4	KIT
VANDETANIB	4	KIT
BOSUTINIB	4	KIT
BRIGATINIB	4	KIT
PEXIDARTINIB	4	KIT
PAZOPANIB	4	KIT
NINTEDANIB	4	KIT
SUNITINIB	4	KIT
DASATINIB	4	KIT
ERLOTINIB	4	KIT
QUIZARTINIB	4	KIT
CRIZOTINIB	4	KIT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KIT, CACNA1E
B	Phased (≥1) drug, not yet approved	1	PRPF31
C	Druggable family + PDB, no drug	1	ABCA1
D	Druggable family + AlphaFold only, no drug	3	OR51Q1, ABCA2, MOCS1
E	Difficult family or no structure, no drug	6	NAV3, CDSN, EYS, SPMIP2, MEGF6, MSH5

Undrugged target profiles

10 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EYS	0	PRPF31
OR51Q1	0	—
NAV3	0	—
CDSN	0	—
SPMIP2	0	—
ABCA1	2	—
ABCA2	0	—
MEGF6	0	—
MOCS1	0	—
MSH5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	11
Not specified	8
PHASE1	4
PHASE1/PHASE2	2
PHASE4	1
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01297777	PHASE4	COMPLETED	Imatinib in KIT-negative Systemic Mastocytosis
NCT01602939	PHASE2/PHASE3	UNKNOWN	Cladribine Plus Pegylated Interpheron Alfa-2a in Systemic Mastocytosis
NCT03401060	PHASE3	COMPLETED	Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis
NCT04996875	PHASE2	RECRUITING	(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis
NCT00109707	PHASE1/PHASE2	COMPLETED	A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies
NCT00171912	PHASE2	COMPLETED	Imatinib Mesylate in Patients With Various Types of Malignancies Involving Activated Tyrosine Kinase Enzymes
NCT00449748	PHASE2	COMPLETED	Everolimus (RAD001) as Therapy for Patients With Systemic Mastocytosis
NCT00493129	PHASE2	COMPLETED	Ontak (Denileukin Diftitox) in Patients With Systemic Mastocytosis (SM)
NCT00918931	PHASE2	TERMINATED	Obatoclax for Systemic Mastocytosis
NCT00979160	PHASE2	UNKNOWN	Evaluation of Response of Dasatinib to Treat Mastocytosis
NCT01807598	PHASE2	COMPLETED	Brentuximab Vedotin in Treating Patients With Advanced Systemic Mastocytosis or Mast Cell Leukemia
NCT02415608	PHASE2	TERMINATED	Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis
NCT02478957	PHASE2	COMPLETED	Treatment of Indolent Systemic Mastocytosis With PA101
NCT03214666	PHASE1/PHASE2	TERMINATED	GTB-3550 Tri-Specific Killer Engager (TriKE®) for High Risk Hematological Malignancies
NCT03580655	PHASE2	COMPLETED	(PATHFINDER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis
NCT03739606	PHASE2	WITHDRAWN	Flotetuzumab in Treating Patients With Recurrent or Refractory CD123 Positive Blood Cancer
NCT02561988	PHASE1	COMPLETED	(EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
NCT02571036	PHASE1	COMPLETED	A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies
NCT04681105	PHASE1	COMPLETED	Flotetuzumab for the Treatment of Relapsed or Refractory Advanced CD123-Positive Hematological Malignancies
NCT05609942	PHASE1	TERMINATED	Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies
NCT07142473	Not specified	RECRUITING	Mastocytosis From Pediatric Age to Adulthood: Local Registry of Cutaneous and Systemic Mastocytosis
NCT07562542	Not specified	RECRUITING	Peripheral Blood KIT-D816V Mutation in Adult Systemic Mastocytosis
NCT01334996	Not specified	COMPLETED	Use of Tamoxifen in Systemic Mastocytosis
NCT02380222	Not specified	COMPLETED	Patient-Reported Outcome Questionnaire for Systemic Mastocytosis
NCT02441166	Not specified	COMPLETED	Diagnostic Value of Bone Marrow Tryptase in Systemic Mastocytosis
NCT04695431	Not specified	COMPLETED	Retrospective Study Assessing the Effect of Avapritinib Versus Best Available Therapy in Patients With AdvSM
NCT04978740	Not specified	COMPLETED	Ocular and Palpebral Manifestations of Mastocytosis (MOOMA)
NCT05219266	Not specified	NO_LONGER_AVAILABLE	Managed Access Programs for PKC412, Midostaurin

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IMATINIB	4	4
AVAPRITINIB	4	2
BRENTUXIMAB VEDOTIN	4	1
CLADRIBINE	4	1
DENOSUMAB	4	1
IBRUTINIB	4	1
MIDOSTAURIN	4	1
NILOTINIB	4	1
RANITIDINE	4	1
RIPRETINIB	4	1
BEZUCLASTINIB	3	1
OBATOCLAX MESYLATE	3	1
ELENESTINIB	2	1
FLOTETUZUMAB	2	1
CHEMBL4776881	0	1
CHEMBL3647964	0	1
CHEMBL4466205	0	1
CHEMBL4790597	0	1
CHEMBL5199540	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 8 predictive associations from 10 curated evidence items; also 6 oncogenic, 1 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
KIT D816V	Avapritinib	Sensitivity/Response	CIViC A	EID11274
NOT KIT D816V AND ( KIT V560G OR KIT D816Y OR KIT D816F )	Imatinib Mesylate	Sensitivity/Response	CIViC B	EID11163 +1
KIT D816V	Midostaurin	Sensitivity/Response	CIViC B	EID1725
NOT KIT D816V	Imatinib	Sensitivity/Response	CIViC B	EID11158
KIT D816V	Imatinib	Resistance	CIViC B	EID11160
NOT KIT D816V	Imatinib Mesylate	Sensitivity/Response	CIViC C	EID11164 +1
NOT KIT D816V AND KIT F522C	Imatinib Mesylate	Sensitivity/Response	CIViC C	EID11366
NOT KIT D816V AND v::PDGFRB Fusion	Imatinib Mesylate	Sensitivity/Response	CIViC C	EID11368