Kleefstra syndrome 1

Summary

Kleefstra syndrome 1 (MONDO:0027407) is a disease caused by EHMT1 (GenCC Definitive), with 13 cohort genes.

At a glance

• Causal gene: EHMT1 (GenCC Definitive)
• Cohort genes: 13
• ClinVar variants: 2,179

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Kleefstra syndrome 1
Mondo ID	MONDO:0027407
MeSH	C563043
OMIM	610253
DOID	DOID:0060352, DOID:0070075
NCIT	C129976
SNOMED CT	724207001
UMLS	C0795833
MedGen	208639
GARD	0025497
Is cancer (heuristic)	no

Also known as: 9q-syndrome · chromosome 9q34.3 deletion syndrome · Kleefstra syndrome · Kleefstra syndrome 1 · KLEFS1

Data availability: 2,179 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Kleefstra syndrome › Kleefstra syndrome 1

Related subtypes (2): Kleefstra syndrome due to a point mutation, Kleefstra syndrome 2

Subtypes (1): Kleefstra syndrome due to 9q34 microdeletion

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

600 retrieved; paginated sample, class counts are floors:

349 likely benign, 109 uncertain significance, 57 conflicting classifications of pathogenicity, 41 benign, 23 pathogenic, 13 benign/likely benign, 7 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073969	NC_000009.11:g.(?140513481)(141016451_?)del	CACNA1B	Pathogenic	criteria provided, single submitter
1073970	NC_000009.11:g.(?140622791)(141016451_?)del	CACNA1B	Pathogenic	criteria provided, single submitter
1031404	NM_024757.5(EHMT1):c.3000del (p.Asp1001fs)	EHMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1048612	NM_024757.5(EHMT1):c.1502-2A>G	EHMT1	Pathogenic	criteria provided, single submitter
1073971	NC_000009.11:g.(?140646763)(140729425_?)del	EHMT1	Pathogenic	criteria provided, single submitter
1074863	NM_024757.5(EHMT1):c.2825dup (p.Leu943fs)	EHMT1	Pathogenic	criteria provided, single submitter
1076531	NM_024757.5(EHMT1):c.2161del (p.Glu721fs)	EHMT1	Pathogenic	criteria provided, single submitter
1285209	NM_024757.5(EHMT1):c.2929C>T (p.Gln977Ter)	EHMT1	Pathogenic	criteria provided, single submitter
1285440	NM_024757.5(EHMT1):c.3012_3016del (p.Pro1005fs)	EHMT1	Pathogenic	criteria provided, single submitter
1285498	NM_024757.5(EHMT1):c.575_581del (p.Pro192fs)	EHMT1	Pathogenic	criteria provided, single submitter
1285594	NM_024757.5(EHMT1):c.1501+1del	EHMT1	Pathogenic	criteria provided, single submitter
128978	NM_024757.5(EHMT1):c.2426C>T (p.Pro809Leu)	EHMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1352642	NM_024757.5(EHMT1):c.784C>T (p.Gln262Ter)	EHMT1	Pathogenic	criteria provided, single submitter
1391038	NM_024757.5(EHMT1):c.3482C>G (p.Ser1161Ter)	EHMT1	Pathogenic	criteria provided, single submitter
1394346	NM_024757.5(EHMT1):c.3393C>A (p.Tyr1131Ter)	EHMT1	Pathogenic	criteria provided, single submitter
1431672	NM_024757.5(EHMT1):c.162del (p.Asn55fs)	EHMT1	Pathogenic	criteria provided, single submitter
1453870	NM_024757.5(EHMT1):c.3579del (p.Asn1194fs)	EHMT1	Pathogenic	criteria provided, single submitter
1459627	NC_000009.11:g.(?140513481)(140513521_?)del	EHMT1	Pathogenic	criteria provided, single submitter
1684279	NM_024757.5(EHMT1):c.2625del (p.Pro876_Met877insTer)	EHMT1	Pathogenic	criteria provided, single submitter
1685762	NM_024757.5(EHMT1):c.1292_1296del (p.Gly431fs)	EHMT1	Pathogenic	criteria provided, single submitter
1685763	NM_024757.5(EHMT1):c.2018+1G>A	EHMT1	Pathogenic	criteria provided, single submitter
1685764	NM_024757.5(EHMT1):c.3310G>T (p.Glu1104Ter)	EHMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1708114	NM_024757.5(EHMT1):c.2799del (p.His933fs)	EHMT1	Pathogenic	criteria provided, single submitter
1033181	NM_170606.3(KMT2C):c.8543del (p.Asn2848fs)	KMT2C	Pathogenic	criteria provided, multiple submitters, no conflicts
1067492	NC_000009.11:g.(?140605409)(140605492_?)dup	EHMT1	Likely pathogenic	criteria provided, single submitter
1068268	NM_024757.5(EHMT1):c.50_85+60del	EHMT1	Likely pathogenic	criteria provided, single submitter
1338984	NM_024757.5(EHMT1):c.2382+1G>A	EHMT1	Likely pathogenic	criteria provided, single submitter
1341714	NC_000009.12:g.137661384_137714409del	EHMT1	Likely pathogenic	criteria provided, single submitter
1703065	NM_024757.5(EHMT1):c.3610del (p.Glu1204fs)	EHMT1	Likely pathogenic	criteria provided, single submitter
1709070	NM_024757.5(EHMT1):c.1180del (p.Glu394fs)	EHMT1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EHMT1	Definitive	Autosomal dominant	Kleefstra syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EHMT1	Orphanet:261652	Kleefstra syndrome due to a point mutation
EHMT1	Orphanet:96147	Kleefstra syndrome due to 9q34 microdeletion
ZMYM2	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2C	Orphanet:261652	Kleefstra syndrome due to a point mutation
CACNA1B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ABCA2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ABCC9	Orphanet:130	Brugada syndrome
ABCC9	Orphanet:1517	Cantú syndrome
ABCC9	Orphanet:154	Familial isolated dilated cardiomyopathy
ABCC9	Orphanet:334	Hereditary atrial fibrillation

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EHMT1	HGNC:24650	ENSG00000181090	Q9H9B1	Histone-lysine N-methyltransferase EHMT1	gencc,clinvar
NOXA1	HGNC:10668	ENSG00000188747	Q86UR1	NADPH oxidase activator 1	clinvar
ZMYM2	HGNC:12989	ENSG00000121741	Q9UBW7	Zinc finger MYM-type protein 2	clinvar
KMT2C	HGNC:13726	ENSG00000055609	Q8NEZ4	Histone-lysine N-methyltransferase 2C	clinvar
CACNA1B	HGNC:1389	ENSG00000148408	Q00975	Voltage-dependent N-type calcium channel subunit alpha-1B	clinvar
ANAPC2	HGNC:19989	ENSG00000176248	Q9UJX6	Anaphase-promoting complex subunit 2	clinvar
TOR4A	HGNC:25981	ENSG00000198113	Q9NXH8	Torsin-4A	clinvar
ARRDC1	HGNC:28633	ENSG00000197070	Q8N5I2	Arrestin domain-containing protein 1	clinvar
ABCA2	HGNC:32	ENSG00000107331	Q9BZC7	ATP-binding cassette sub-family A member 2	clinvar
RNF224	HGNC:41912	ENSG00000233198	P0DH78	RING finger protein 224	clinvar
ABCC9	HGNC:60	ENSG00000069431	O60706	ATP-binding cassette sub-family C member 9	clinvar
NR1I3	HGNC:7969	ENSG00000143257	Q14994	Nuclear receptor subfamily 1 group I member 3	clinvar
PAEP	HGNC:8573	ENSG00000122133	P09466	Glycodelin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EHMT1	Histone-lysine N-methyltransferase EHMT1	Histone methyltransferase that specifically mono-, di- and trimethylates ‘Lys-9’ of histone H3 (H3K9me1, H3K9me2 and H3K9me3, respectively) in euchromatin.
NOXA1	NADPH oxidase activator 1	Functions as an activator of NOX1, a superoxide-producing NADPH oxidase.
ZMYM2	Zinc finger MYM-type protein 2	Involved in the negative regulation of transcription.
KMT2C	Histone-lysine N-methyltransferase 2C	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).
CACNA1B	Voltage-dependent N-type calcium channel subunit alpha-1B	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
ANAPC2	Anaphase-promoting complex subunit 2	Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of th…
ARRDC1	Arrestin domain-containing protein 1	Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates.
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.
ABCC9	ATP-binding cassette sub-family C member 9	Subunit of ATP-sensitive potassium channels (KATP).
NR1I3	Nuclear receptor subfamily 1 group I member 3	Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes.
PAEP	Glycodelin	Glycoprotein that regulates critical steps during fertilization and also has immunomonomodulatory effects.

Protein-family classification

Druggable: 4 · Difficult: 5 · Unknown: 4 · Druggable fraction: 0.31

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
Nuclear receptor	1	29.7×	0.100
Ion channel	1	8.6×	0.221
Scaffold/PPI	2	2.7×	0.243
Transcription factor	3	1.9×	0.243
Other/Unknown	4	0.6×	0.982

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EHMT1	Scaffold/PPI	no	2.1.1.367	SET_dom, Ankyrin_rpt, Pre-SET_dom
NOXA1	Scaffold/PPI	no		PB1_dom, SH3_domain, TPR-like_helical_dom_sf
ZMYM2	Transcription factor	no		Znf_MYM, TRASH_dom, ZMYM2-like_C
KMT2C	Transcription factor	no		HMGI/Y_DNA-bd_CS, SET_dom, Znf_RING
CACNA1B	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_N_a1su
ANAPC2	Other/Unknown	no		ANAPC2_C, Cullin_homology, Cullin_homology_sf
TOR4A	Other/Unknown	no		AAA+_ATPase, Torsin, P-loop_NTPase
ARRDC1	Other/Unknown	no		Arrestin-like_N, Arrestin-like_C, Arrestin-like_C_sf
ABCA2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
RNF224	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
ABCC9	Transporter	yes		ABCC8/9, ABCC9, ABC_transporter-like_ATP-bd
NR1I3	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PAEP	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, Lipocalin, Blactoglobulin

Expression context

Cohort genes with no expression data: 0.

10 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	4
left testis	2
mucosa of transverse colon	2
oocyte	2
right hemisphere of cerebellum	2
granulocyte	2
male germ line stem cell (sensu Vertebrata) in testis	2
adrenal tissue	1
sural nerve	1
pancreatic ductal cell	1
secondary oocyte	1
sperm	1
caput epididymis	1
upper arm skin	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
postcentral gyrus	1
buccal mucosa cell	1
lower esophagus mucosa	1
C1 segment of cervical spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EHMT1	257	ubiquitous	marker	sural nerve, adrenal tissue, left testis
NOXA1	229	ubiquitous	marker	pancreatic ductal cell, mucosa of transverse colon, right uterine tube
ZMYM2	294	ubiquitous	marker	sperm, oocyte, secondary oocyte
KMT2C	261	ubiquitous	marker	oocyte, caput epididymis, upper arm skin
CACNA1B	146	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, postcentral gyrus
ANAPC2	237	ubiquitous	yes	right uterine tube, right hemisphere of cerebellum, left testis
TOR4A	184	ubiquitous	marker	buccal mucosa cell, mucosa of transverse colon, granulocyte
ARRDC1	246	ubiquitous	marker	lower esophagus mucosa, granulocyte, right uterine tube
ABCA2	234	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum
RNF224	117		yes	right uterine tube, pituitary gland, adenohypophysis
ABCC9	195	broad	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
NR1I3	171	tissue_specific	yes	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
PAEP	107	tissue_specific	marker	decidua, seminal vesicle, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EHMT1	3,590
KMT2C	3,321
ZMYM2	2,565
CACNA1B	2,441
ANAPC2	2,288
ABCC9	1,728
ABCA2	1,678
PAEP	1,476
NR1I3	1,460
ARRDC1	823

Intra-cohort edges

A	B	Sources
ARRDC1	ZMYM2	biogrid_interaction, intact
CACNA1B	EHMT1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EHMT1	Q9H9B1	23
ANAPC2	Q9UJX6	23
KMT2C	Q8NEZ4	9
CACNA1B	Q00975	7
NR1I3	Q14994	2
NOXA1	Q86UR1	1
PAEP	P09466	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABCC9	O60706	81.72
TOR4A	Q9NXH8	79.35
ARRDC1	Q8N5I2	78.34
RNF224	P0DH78	78.07
ABCA2	Q9BZC7	71.46
ZMYM2	Q9UBW7	61.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 90. Enrichment computed across 13 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	571.0×	0.053	ABCC9
Transcriptional Regulation by VENTX	2	53.1×	0.053	EHMT1, ANAPC2
PKMTs methylate histone lysines	2	32.2×	0.053	EHMT1, KMT2C
ATP sensitive Potassium channels	1	285.5×	0.063	ABCC9
ABC-family protein mediated transport	2	24.3×	0.063	ABCA2, ABCC9
Senescence-Associated Secretory Phenotype (SASP)	2	19.9×	0.064	EHMT1, ANAPC2
Presynaptic depolarization and calcium channel opening	1	95.2×	0.081	CACNA1B
WNT5:FZD7-mediated leishmania damping	1	95.2×	0.081	NOXA1
Inwardly rectifying K+ channels	1	71.4×	0.081	ABCC9
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1	63.4×	0.081	ANAPC2
Signaling by cytosolic FGFR1 fusion mutants	1	63.4×	0.081	ZMYM2
ABC transporters in lipid homeostasis	1	60.1×	0.081	ABCA2
Signaling by FLT3 fusion proteins	1	57.1×	0.081	ZMYM2
Phosphorylation of the APC/C	1	54.4×	0.081	ANAPC2
Regulation of TP53 Activity through Methylation	1	54.4×	0.081	EHMT1
Inactivation of APC/C via direct inhibition of the APC/C complex	1	51.9×	0.081	ANAPC2
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	1	51.9×	0.081	ANAPC2
Aberrant regulation of mitotic exit in cancer due to RB1 defects	1	51.9×	0.081	ANAPC2
APC/C:Cdc20 mediated degradation of Cyclin B	1	45.7×	0.081	ANAPC2
RHO GTPases Activate NADPH Oxidases	1	45.7×	0.081	NOXA1
ABC transporter disorders	1	43.9×	0.081	ABCC9
Activation of HOX genes during differentiation	1	43.9×	0.081	KMT2C
APC-Cdc20 mediated degradation of Nek2A	1	42.3×	0.081	ANAPC2
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1	42.3×	0.081	ANAPC2
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	1	40.8×	0.081	ANAPC2
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	40.8×	0.081	ANAPC2
Diseases of mitotic cell cycle	1	39.4×	0.081	ANAPC2
Neuronal System	2	8.8×	0.081	CACNA1B, ABCC9
APC/C:Cdc20 mediated degradation of mitotic proteins	1	35.7×	0.082	ANAPC2
APC/C-mediated degradation of cell cycle proteins	1	33.6×	0.082	ANAPC2

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
negative regulation of intracellular cholesterol transport	1	1532.0×	0.012	ABCA2
negative regulation of phospholipid biosynthetic process	1	1532.0×	0.012	ABCA2
negative regulation of sphingolipid biosynthetic process	1	1532.0×	0.012	ABCA2
regulation of protein localization to cell periphery	1	1532.0×	0.012	ABCA2
negative regulation of steroid metabolic process	1	766.0×	0.012	ABCA2
ceramide translocation	1	766.0×	0.012	ABCA2
extracellular vesicle biogenesis	1	766.0×	0.012	ARRDC1
negative regulation of white fat cell differentiation	1	766.0×	0.012	EHMT1
regulation of post-translational protein modification	1	766.0×	0.012	ABCA2
negative regulation of sperm capacitation	1	766.0×	0.012	PAEP
response to hydrogen sulfide	1	766.0×	0.012	ABCC9
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	766.0×	0.012	ABCA2
regulation of binding of sperm to zona pellucida	1	766.0×	0.012	PAEP
extracellular transport	1	510.7×	0.012	ARRDC1
positive regulation of low-density lipoprotein particle receptor catabolic process	1	510.7×	0.012	ABCA2
beige fat cell differentiation	1	510.7×	0.012	EHMT1
positive regulation of calcium ion-dependent exocytosis of neurotransmitter	1	510.7×	0.012	CACNA1B
transport across blood-brain barrier	2	32.6×	0.012	ABCA2, ABCC9
transmembrane transport	2	30.6×	0.012	ABCA2, ABCC9
ganglioside metabolic process	1	383.0×	0.014	ABCA2
regulation of intracellular cholesterol transport	1	383.0×	0.014	ABCA2
regulation of respiratory burst	1	383.0×	0.014	NOXA1
oxygen metabolic process	1	383.0×	0.014	ABCC9
sphingomyelin metabolic process	1	306.4×	0.015	ABCA2
peptidyl-lysine dimethylation	1	306.4×	0.015	EHMT1
positive regulation of amyloid precursor protein biosynthetic process	1	306.4×	0.015	ABCA2
intracellular sphingolipid homeostasis	1	306.4×	0.015	ABCA2
regulation of hydrogen peroxide metabolic process	1	255.3×	0.015	NOXA1
response to fungicide	1	255.3×	0.015	EHMT1
cellular response to chemical stress	1	255.3×	0.015	ABCC9

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 9

Druggability breadth: 5 of 13 evidence-associated genes (38%) 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
EHMT1	DISULFIRAM
CACNA1B	NIFEDIPINE
ABCC9	PINACIDIL ANHYDROUS
NR1I3	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR1I3	26	4
CACNA1B	23	4
EHMT1	5	4
ABCC9	5	4
NOXA1	0	0
ZMYM2	0	0
KMT2C	0	0
ANAPC2	0	0
TOR4A	0	0
ARRDC1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DISULFIRAM	4	EHMT1
NIFEDIPINE	4	CACNA1B
NIMODIPINE	4	CACNA1B
TACRINE	4	CACNA1B
IMIPRAMINE	4	CACNA1B
AMOXAPINE	4	CACNA1B
MAPROTILINE	4	CACNA1B
CLOMIPRAMINE	4	CACNA1B
NORTRIPTYLINE	4	CACNA1B
MIBEFRADIL	4	CACNA1B
ZICONOTIDE	4	CACNA1B
AMITRIPTYLINE	4	CACNA1B
PROMETHAZINE	4	CACNA1B
TRIMIPRAMINE	4	CACNA1B
PROTRIPTYLINE	4	CACNA1B
CYCLOBENZAPRINE	4	CACNA1B
DESIPRAMINE	4	CACNA1B
PINACIDIL ANHYDROUS	4	ABCC9
GLYBURIDE	4	ABCC9
PROPAFENONE	4	ABCC9
CLOTRIMAZOLE	4	NR1I3
SIMVASTATIN	4	NR1I3
AMOXICILLIN	4	NR1I3
RIMONABANT	4	NR1I3
ACETAMINOPHEN	4	NR1I3
ROSIGLITAZONE	4	NR1I3
REPAGLINIDE	4	NR1I3
TOLCAPONE	4	NR1I3
DICLOFENAC	4	NR1I3
GLIMEPIRIDE	4	NR1I3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EHMT1	181	Binding:180, ADMET:1
NR1I3	163	Binding:131, ADMET:26, Functional:6
CACNA1B	135	Binding:110, Functional:25
ABCC9	61	Functional:46, Binding:15
KMT2C	29	Binding:29

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EHMT1	2.1.1.367, 2.1.1.368	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine9 N-dimethyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EHMT1	181
CACNA1B	135
NR1I3	163

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

30 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)
DISULFIRAM	4	EHMT1
NIFEDIPINE	4	CACNA1B
NIMODIPINE	4	CACNA1B
TACRINE	4	CACNA1B
IMIPRAMINE	4	CACNA1B
AMOXAPINE	4	CACNA1B
MAPROTILINE	4	CACNA1B
CLOMIPRAMINE	4	CACNA1B
NORTRIPTYLINE	4	CACNA1B
MIBEFRADIL	4	CACNA1B
ZICONOTIDE	4	CACNA1B
AMITRIPTYLINE	4	CACNA1B
PROMETHAZINE	4	CACNA1B
TRIMIPRAMINE	4	CACNA1B
PROTRIPTYLINE	4	CACNA1B
CYCLOBENZAPRINE	4	CACNA1B
DESIPRAMINE	4	CACNA1B
PINACIDIL ANHYDROUS	4	ABCC9
GLYBURIDE	4	ABCC9
PROPAFENONE	4	ABCC9
CLOTRIMAZOLE	4	NR1I3
SIMVASTATIN	4	NR1I3
AMOXICILLIN	4	NR1I3
RIMONABANT	4	NR1I3
ACETAMINOPHEN	4	NR1I3
ROSIGLITAZONE	4	NR1I3
REPAGLINIDE	4	NR1I3
TOLCAPONE	4	NR1I3
DICLOFENAC	4	NR1I3
GLIMEPIRIDE	4	NR1I3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	EHMT1, CACNA1B, ABCC9, NR1I3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ABCA2
E	Difficult family or no structure, no drug	8	NOXA1, ZMYM2, KMT2C, ANAPC2, TOR4A, ARRDC1, RNF224, PAEP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NOXA1	0	—
ZMYM2	0	—
KMT2C	29	—
ANAPC2	0	—
TOR4A	0	—
ARRDC1	0	—
ABCA2	0	—
RNF224	0	—
PAEP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.