Acute megakaryoblastic leukemia in down syndrome

Summary

Acute megakaryoblastic leukemia in down syndrome (MONDO:0020526) is a cancer with 8 cohort genes (7 CIViC-evidence somatic drivers; 14 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 8
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acute megakaryoblastic leukemia in down syndrome
Mondo ID	MONDO:0020526
Orphanet	99887
UMLS	C5925108
MedGen	1863778
GARD	0019697
Is cancer (heuristic)	yes

Also known as: DS-AMKL

Data availability: 14 ClinVar variants · 14 cell lines.

Disease family

Classification path: cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › leukemia › myeloid leukemia › acute myeloid leukemia › acute myeloid leukemia by FAB classification › acute megakaryoblastic leukemia › acute megakaryoblastic leukemia in down syndrome

Related subtypes (4): acute megakaryoblastic leukemia without down syndrome, childhood acute megakaryoblastic leukemia, myeloid leukemia associated with down syndrome, acute megakaryoblastic leukemia in adult

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

14 retrieved; paginated sample, class counts are floors:

6 pathogenic, 5 likely pathogenic, 2 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
465134	NM_002049.4(GATA1):c.89C>G (p.Ser30Ter)	GATA1	Pathogenic	criteria provided, multiple submitters, no conflicts
998066	NM_002049.4(GATA1):c.175_193dup (p.Asp65fs)	GATA1	Pathogenic	criteria provided, single submitter
998069	NM_002049.4(GATA1):c.115_116insGGGGCTTGGATGCAGCAGCTTCCTGCACTGCCCCGAGCACAGCCACCGCTGCAGCTGCGGCCTG (p.Glu39delinsGlyGlyLeuAspAlaAlaAlaSerCysThrAlaProSerThrAlaThrAlaAlaAlaAlaAlaTer)	GATA1	Pathogenic	criteria provided, single submitter
998072	NM_002049.4(GATA1):c.142_149dup (p.Ser51fs)	GATA1	Pathogenic	criteria provided, single submitter
998073	NM_002049.4(GATA1):c.159_171dup (p.Ala58fs)	GATA1	Pathogenic	criteria provided, single submitter
998076	NM_002049.4(GATA1):c.219A>G (p.Pro73=)	GATA1	Pathogenic	criteria provided, single submitter
13901	NM_002524.5(NRAS):c.38G>A (p.Gly13Asp)	NRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
998071	NM_015355.4(SUZ12):c.1150_1151del (p.Leu385fs)	SUZ12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
998068	NM_006565.4(CTCF):c.1502_1503dup (p.Tyr502fs)	CTCF	Likely pathogenic	criteria provided, single submitter
998070	NM_006565.4(CTCF):c.1640_1650delinsT (p.Asp547fs)	CTCF	Likely pathogenic	criteria provided, single submitter
998074	NM_002227.4(JAK1):c.2347C>T (p.Leu783Phe)	JAK1	Likely pathogenic	criteria provided, single submitter
998075	NM_001195427.2(SRSF2):c.284C>G (p.Pro95Arg)	MFSD11	Likely pathogenic	criteria provided, single submitter
998067	NM_006265.3(RAD21):c.9C>A (p.Tyr3Ter)	RAD21	Likely pathogenic	criteria provided, single submitter
13341	NM_002834.5(PTPN11):c.1232C>T (p.Thr411Met)	PTPN11	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 27 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CTCF	LoF	ALL,BRCA,HNSC,UCEC	CIViC #8508
SUZ12	Act	AML,PRAD,SARCNOS
GATA1			CIViC #2188
JAK1	LoF	ALL,BRCA,MLYM,OVT,PRAD,PROSTATE,STOMACH,UCEC	CIViC #3090
NRAS	Act	ALL,AML,ANGS,CHOL,CLLSLL,COAD,COADREAD,GBM,HCC,LGGNOS,LUAD,LUSC,MEL,MGCT,NPC,OVT,PCM,PROSTATE,SKCM,THYM,UCEC,WDTC	CIViC #36
PTPN11	Act	ALL,AML,CLLSLL,COADREAD,GBM,LGGNOS,NBL,PAST,PCM	CIViC #4685
RAD21	LoF	AML,LUSC

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTCF	Orphanet:363611	CTCF-related neurodevelopmental disorder
SUZ12	Orphanet:213711	Endometrial stromal sarcoma
SUZ12	Orphanet:3447	Weaver syndrome
SUZ12	Orphanet:659463	Imagawa-Matsumoto syndrome
GATA1	Orphanet:124	Diamond-Blackfan anemia
GATA1	Orphanet:231393	Beta-thalassemia-X-linked thrombocytopenia syndrome
GATA1	Orphanet:363727	X-linked dyserythropoietic anemia with abnormal platelets and neutropenia
GATA1	Orphanet:420611	Transient myeloproliferative syndrome
GATA1	Orphanet:67044	Thrombocytopenia with congenital dyserythropoietic anemia
GATA1	Orphanet:79277	Congenital erythropoietic porphyria
GATA1	Orphanet:86849	Acute basophilic leukemia
GATA1	Orphanet:99887	Acute megakaryoblastic leukemia in children with Down syndrome
JAK1	Orphanet:574957	Mendelian susceptibility to mycobacterial diseases due to partial JAK1 deficiency
JAK1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia
RAD21	Orphanet:199	Cornelia de Lange syndrome
RAD21	Orphanet:502	Trichorhinophalangeal syndrome type 2

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CTCF	HGNC:13723	ENSG00000102974	P49711	Transcriptional repressor CTCF	clinvar
SUZ12	HGNC:17101	ENSG00000178691	Q15022	Polycomb protein SUZ12	clinvar
MFSD11	HGNC:25458	ENSG00000092931	O43934	UNC93-like protein MFSD11	clinvar
GATA1	HGNC:4170	ENSG00000102145	P15976	Erythroid transcription factor	clinvar
JAK1	HGNC:6190	ENSG00000162434	P23458	Tyrosine-protein kinase JAK1	clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar
RAD21	HGNC:9811	ENSG00000164754	O60216	Double-strand-break repair protein rad21 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTCF	Transcriptional repressor CTCF	Chromatin binding factor that binds to DNA sequence specific sites and regulates the 3D structure of chromatin.
SUZ12	Polycomb protein SUZ12	Polycomb group (PcG) protein.
GATA1	Erythroid transcription factor	Transcriptional activator or repressor which serves as a general switch factor for erythroid development.
JAK1	Tyrosine-protein kinase JAK1	Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.
RAD21	Double-strand-break repair protein rad21 homolog	As a member of the cohesin complex, involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is essential for proper chromosome segregation, post-replicative DNA rep…

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.38

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
Ion channel	1	13.9×	0.152
Phosphatase	1	10.5×	0.152
Transcription factor	3	3.1×	0.152
Kinase	1	3.5×	0.318
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTCF	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger_PRDM4/PRDM1/PRDM14
SUZ12	Transcription factor	no		Polycomb_protein_VEFS-Box, Znf_SUZ12
MFSD11	Ion channel	yes		Ion_channel_UNC-93, MFS_trans_sf, UNC-93-like_regulator
GATA1	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, Transcription_factor_GATA
JAK1	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
RAD21	Other/Unknown	no		Rad21/Rec8_C_eu, Rad21_Rec8_N, ScpA-like_C

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
buccal mucosa cell	2
trabecular bone tissue	2
endometrium epithelium	1
mucosa of paranasal sinus	1
adrenal tissue	1
primordial germ cell in gonad	1
blood	1
bone marrow	1
calcaneal tendon	1
skin of hip	1
type B pancreatic cell	1
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1
superficial temporal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTCF	297	ubiquitous	marker	ventricular zone, ganglionic eminence, endometrium epithelium
SUZ12	288	ubiquitous	marker	trabecular bone tissue, mucosa of paranasal sinus, buccal mucosa cell
MFSD11	244	ubiquitous	marker	buccal mucosa cell, adrenal tissue, primordial germ cell in gonad
GATA1	138	tissue_specific	marker	trabecular bone tissue, blood, bone marrow
JAK1	295	ubiquitous	marker	type B pancreatic cell, skin of hip, calcaneal tendon
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus
RAD21	301	ubiquitous	marker	ventricular zone, ganglionic eminence, superficial temporal artery

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NRAS	7,598
PTPN11	6,009
CTCF	5,713
JAK1	5,229
RAD21	5,042
GATA1	4,810
SUZ12	4,349
MFSD11	1,076

Intra-cohort edges

A	B	Sources
CTCF	RAD21	string_interaction
CTCF	SUZ12	string_interaction
NRAS	PTPN11	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
JAK1	P23458	51
RAD21	O60216	36
NRAS	P01111	35
SUZ12	Q15022	30
CTCF	P49711	21
GATA1	P15976	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MFSD11	O43934	87.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 192. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAPK1 (ERK2) activation	2	326.3×	0.001	JAK1, PTPN11
MAPK3 (ERK1) activation	2	296.6×	0.001	JAK1, PTPN11
Interleukin-6 signaling	2	271.9×	0.001	JAK1, PTPN11
Activated NTRK2 signals through FRS2 and FRS3	2	271.9×	0.001	NRAS, PTPN11
Regulation of IFNG signaling	2	233.1×	0.001	JAK1, PTPN11
Signaling by FLT3 ITD and TKD mutants	2	217.5×	0.001	NRAS, PTPN11
Tie2 Signaling	2	171.7×	0.001	NRAS, PTPN11
Signaling by CSF3 (G-CSF)	2	163.1×	0.001	JAK1, PTPN11
FRS-mediated FGFR3 signaling	2	155.4×	0.001	NRAS, PTPN11
FRS-mediated FGFR4 signaling	2	141.9×	0.002	NRAS, PTPN11
FRS-mediated FGFR1 signaling	2	130.5×	0.002	NRAS, PTPN11
FRS-mediated FGFR2 signaling	2	125.5×	0.002	NRAS, PTPN11
Regulation of IFNA/IFNB signaling	2	125.5×	0.002	JAK1, PTPN11
Interleukin-20 family signaling	2	120.8×	0.002	JAK1, PTPN11
Downstream signal transduction	2	108.8×	0.002	NRAS, PTPN11
FLT3 Signaling	2	98.9×	0.002	NRAS, PTPN11
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	90.6×	0.002	JAK1, PTPN11
Signaling by SCF-KIT	2	70.9×	0.004	NRAS, PTPN11
Interferon alpha/beta signaling	2	43.5×	0.009	JAK1, PTPN11
Signaling by RAS GAP mutants	1	543.8×	0.017	NRAS
Signaling by RAS GTPase mutants	1	543.8×	0.017	NRAS
Activation of anterior HOX genes in hindbrain development during early embryogenesis	2	26.1×	0.021	CTCF, SUZ12
SARS-CoV-2 activates/modulates innate and adaptive immune responses	2	25.5×	0.021	JAK1, PTPN11
Activation of RAS in B cells	1	326.3×	0.023	NRAS
MET activates PTPN11	1	326.3×	0.023	PTPN11
Co-inhibition by BTLA	1	326.3×	0.023	PTPN11
RAS signaling downstream of NF1 loss-of-function variants	1	233.1×	0.027	NRAS
Estrogen-stimulated signaling through PRKCZ	1	233.1×	0.027	NRAS
STAT5 Activation	1	233.1×	0.027	PTPN11
SOS-mediated signalling	1	203.9×	0.027	NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chromatin looping	2	300.9×	0.003	CTCF, RAD21
platelet formation	2	175.5×	0.004	GATA1, PTPN11
homeostasis of number of cells within a tissue	2	110.9×	0.007	GATA1, PTPN11
negative regulation of cortisol secretion	1	2106.5×	0.014	PTPN11
negative regulation of growth hormone secretion	1	2106.5×	0.014	PTPN11
regulation of primitive erythrocyte differentiation	1	1053.2×	0.014	GATA1
basophil differentiation	1	1053.2×	0.014	GATA1
microvillus organization	1	1053.2×	0.014	PTPN11
eosinophil fate commitment	1	1053.2×	0.014	GATA1
intestinal epithelial cell migration	1	1053.2×	0.014	PTPN11
chromosome segregation	2	43.4×	0.014	CTCF, RAD21
regulation of definitive erythrocyte differentiation	1	702.2×	0.015	GATA1
cerebellar cortex formation	1	702.2×	0.015	PTPN11
regulation of centromeric sister chromatid cohesion	1	702.2×	0.015	CTCF
regulation of glycoprotein biosynthetic process	1	526.6×	0.015	GATA1
eosinophil differentiation	1	526.6×	0.015	GATA1
establishment of meiotic sister chromatid cohesion	1	526.6×	0.015	RAD21
negative regulation of mitotic metaphase/anaphase transition	1	526.6×	0.015	RAD21
primitive erythrocyte differentiation	1	526.6×	0.015	GATA1
regulation of type I interferon-mediated signaling pathway	1	526.6×	0.015	PTPN11
cytokine-mediated signaling pathway	2	32.7×	0.015	JAK1, PTPN11
ERBB signaling pathway	1	421.3×	0.016	PTPN11
interleukin-11-mediated signaling pathway	1	421.3×	0.016	JAK1
positive regulation of sister chromatid cohesion	1	421.3×	0.016	RAD21
replication-born double-strand break repair via sister chromatid exchange	1	351.1×	0.017	RAD21
establishment of mitotic sister chromatid cohesion	1	300.9×	0.017	RAD21
positive regulation of homotypic cell-cell adhesion	1	300.9×	0.017	JAK1
interleukin-4-mediated signaling pathway	1	300.9×	0.017	JAK1
negative regulation of neutrophil activation	1	300.9×	0.017	PTPN11
myeloid cell apoptotic process	1	263.3×	0.017	GATA1

Therapeutics

Drug target analysis

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

Druggability breadth: 5 of 8 evidence-associated genes (62%) 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
SUZ12	TAZEMETOSTAT
JAK1	FEDRATINIB
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JAK1	68	4
PTPN11	8	4
SUZ12	2	4
NRAS	1	1
CTCF	0	0
MFSD11	0	0
GATA1	0	0
RAD21	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TAZEMETOSTAT	4	SUZ12
FEDRATINIB	4	JAK1
RUXOLITINIB	4	JAK1
TOFACITINIB	4	JAK1
UPADACITINIB	4	JAK1
MOMELOTINIB	4	JAK1
PONATINIB	4	JAK1
RUXOLITINIB PHOSPHATE	4	JAK1
ENTRECTINIB	4	JAK1
PACRITINIB	4	JAK1
TOFACITINIB CITRATE	4	JAK1
BARICITINIB	4	JAK1
CERITINIB	4	JAK1
PEFICITINIB	4	JAK1
FILGOTINIB	4	JAK1
ABROCITINIB	4	JAK1
RITLECITINIB	4	JAK1
DEUCRAVACITINIB	4	JAK1
NINTEDANIB	4	JAK1
SUNITINIB	4	JAK1
CRIZOTINIB	4	JAK1
MIDOSTAURIN	4	JAK1
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ITACITINIB	3	JAK1
BREPOCITINIB	3	JAK1
DELGOCITINIB	3	JAK1
ABIVERTINIB	3	JAK1
POVORCITINIB	3	JAK1
IVARMACITINIB	3	JAK1
DOVITINIB	3	JAK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
JAK1	1,502	Binding:1428, Functional:49, ADMET:24, Toxicity:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
SUZ12	51	Binding:51
NRAS	18	Binding:18
CTCF	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
JAK1	2.7.10.2	non-specific protein-tyrosine kinase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
JAK1	1,502
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
TAZEMETOSTAT	4	SUZ12
FEDRATINIB	4	JAK1
RUXOLITINIB	4	JAK1
TOFACITINIB	4	JAK1
UPADACITINIB	4	JAK1
MOMELOTINIB	4	JAK1
PONATINIB	4	JAK1
RUXOLITINIB PHOSPHATE	4	JAK1
ENTRECTINIB	4	JAK1
PACRITINIB	4	JAK1
TOFACITINIB CITRATE	4	JAK1
BARICITINIB	4	JAK1
CERITINIB	4	JAK1
PEFICITINIB	4	JAK1
FILGOTINIB	4	JAK1
ABROCITINIB	4	JAK1
RITLECITINIB	4	JAK1
DEUCRAVACITINIB	4	JAK1
NINTEDANIB	4	JAK1
SUNITINIB	4	JAK1
CRIZOTINIB	4	JAK1
MIDOSTAURIN	4	JAK1
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ITACITINIB	3	JAK1
BREPOCITINIB	3	JAK1
DELGOCITINIB	3	JAK1
ABIVERTINIB	3	JAK1
POVORCITINIB	3	JAK1
IVARMACITINIB	3	JAK1
DOVITINIB	3	JAK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SUZ12, JAK1, PTPN11
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MFSD11
E	Difficult family or no structure, no drug	3	CTCF, GATA1, RAD21

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CTCF	2	—
MFSD11	0	—
GATA1	0	—
RAD21	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.