Megacolon

Summary

Megacolon (MONDO:0001273) is a disease with 49 cohort genes and 2 clinical trials. The dominant Reactome pathway is Mitochondrial protein import (3 cohort genes).

At a glance

• Cohort genes: 49
• ClinVar variants: 59
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megacolon
Mondo ID	MONDO:0001273
MeSH	D008531
DOID	DOID:11372
ICD-11	1742998538
NCIT	C34810
SNOMED CT	33995003
UMLS	C0025160
MedGen	6285
Is cancer (heuristic)	no

Data availability: 59 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › large intestine disorder › colonic disorder › megacolon

Related subtypes (12): neuronal intestinal dysplasia, functional diarrhea, diverticulitis of colon, cecal disorder, sigmoid disease, functional colonic disease, colitis, colonic neoplasm, colon dysplasia, polyp of colon, Chilaiditi syndrome, colonic duplication

Subtypes (1): toxic megacolon

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

59 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 10 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3769606	NM_014795.4(ZEB2):c.1664del (p.Lys555fs)	ZEB2	Pathogenic	criteria provided, single submitter
974733	NC_000006.11:g.28005012_31683185del	ABCF1	Likely pathogenic	criteria provided, single submitter
974738	NC_000010.10:g.49033586_52417694del	AGAP6	Likely pathogenic	criteria provided, single submitter
974739	NC_000011.10:g.62483829_62531399dup	AHNAK	Likely pathogenic	criteria provided, single submitter
974712	NC_000022.10:g.18861209_21630630del	AIFM3	Likely pathogenic	criteria provided, single submitter
974720	NC_000001.11:g.243800225_243853502del	AKT3	Likely pathogenic	criteria provided, single submitter
974763	NC_000017.10:g.58076721_60362868del	APPBP2	Likely pathogenic	criteria provided, single submitter
974746	NC_000022.10:g.18687210_19060954dup	DGCR2	Likely pathogenic	criteria provided, single submitter
974727	NM_002012.4(FHIT):c.103+32489_103+54184del	FHIT	Likely pathogenic	criteria provided, single submitter
974721	NM_021097.5(SLC8A1):c.1808+9112_1808+31346del	LOC120961747	Likely pathogenic	criteria provided, single submitter
974750	NC_000003.11:g.14406477_14509088dup	SLC6A6	Likely pathogenic	criteria provided, single submitter
267864	46;XY;t(2;13)(p25.2;q31.3)dn		Uncertain significance	criteria provided, single submitter
974714	NC_000023.11:g.3266860_3322912dup		Uncertain significance	criteria provided, single submitter
974715	NC_000023.11:g.95154038_95191395del		Uncertain significance	criteria provided, single submitter
974722	NC_000002.11:g.102658576_102847088dup		Uncertain significance	criteria provided, single submitter
974729	NC_000003.12:g.146056770_146083362dup		Uncertain significance	criteria provided, single submitter
974743	NC_000018.10:g.6454094_6548625dup		Uncertain significance	criteria provided, single submitter
974744	NC_000018.10:g.48229615_48261302dup		Uncertain significance	criteria provided, single submitter
974740	NC_000012.12:g.9092896_9155947dup	A2M	Uncertain significance	criteria provided, single submitter
974754	NC_000007.13:g.4736454_4860123dup	AP5Z1	Uncertain significance	criteria provided, single submitter
974724	NC_000002.12:g.215349854_215435010del	ATIC	Uncertain significance	criteria provided, single submitter
974747	NC_000002.11:g.10664398_10914786dup	ATP6V1C2	Uncertain significance	criteria provided, single submitter
974710	NC_000001.10:g.3776519_4049451dup	C1orf174	Uncertain significance	criteria provided, single submitter
974762	NC_000015.9:g.62409198_62521004dup	C2CD4B	Uncertain significance	criteria provided, single submitter
974730	NC_000004.12:g.158620035_158710228del	C4orf46	Uncertain significance	criteria provided, single submitter
974732	NC_000006.12:g.22008001_22092880del	CASC15	Uncertain significance	criteria provided, single submitter
974764	NC_000018.9:g.65699090_66534856dup	CCDC102B	Uncertain significance	criteria provided, single submitter
974718	NC_000001.11:g.152313740_152351227dup	CCDST	Uncertain significance	criteria provided, single submitter
974758	NC_000008.10:g.95186036_95301703dup	CDH17	Uncertain significance	criteria provided, single submitter
974761	NC_000012.11:g.94767704_94880489del	CEP83	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 45 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RHCE	Orphanet:71275	Rh deficiency syndrome
SLC25A13	Orphanet:247585	Citrullinemia type II
SLC25A13	Orphanet:247598	Neonatal intrahepatic cholestasis due to citrin deficiency
ZEB2	Orphanet:261537	Mowat-Wilson syndrome due to monosomy 2q22
ZEB2	Orphanet:261552	Mowat-Wilson syndrome due to a ZEB2 point mutation
ZEB2	Orphanet:626	Large/giant congenital melanocytic nevus
PCNT	Orphanet:2637	Microcephalic osteodysplastic primordial dwarfism type II
PCNT	Orphanet:808	Seckel syndrome
CEP83	Orphanet:93591	Infantile nephronophthisis
CFTR	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CFTR	Orphanet:48	Congenital bilateral absence of vas deferens
CFTR	Orphanet:498359	Aquagenic palmoplantar keratoderma
CFTR	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:60033	Idiopathic bronchiectasis
CFTR	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria
COL3A1	Orphanet:286	Vascular Ehlers-Danlos syndrome
COL3A1	Orphanet:636941	Vascular Ehlers-Danlos-polymicrogyria syndrome
COL3A1	Orphanet:86	Familial abdominal aortic aneurysm
AP5Z1	Orphanet:306511	Autosomal recessive spastic paraplegia type 48
OTOGL	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
EDN3	Orphanet:388	Hirschsprung disease
EDN3	Orphanet:661	Congenital central hypoventilation syndrome
EDN3	Orphanet:897	Waardenburg-Shah syndrome
ETFDH	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFDH	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type
FHIT	Orphanet:422526	Hereditary clear cell renal cell carcinoma
AKT3	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
AKT3	Orphanet:99802	Hemimegalencephaly
MTX2	Orphanet:647667	Mandibuloacral dysplasia associated to MTX2
ATIC	Orphanet:250977	AICA-ribosiduria
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

49 cohort genes, 47 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	49

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHCE	HGNC:10008	ENSG00000188672	P18577	Blood group Rh(CE) polypeptide	clinvar
SLC25A13	HGNC:10983	ENSG00000004864	Q9UJS0	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	clinvar
SLC6A6	HGNC:11052	ENSG00000131389	P31641	Sodium- and chloride-dependent taurine transporter	clinvar
CRISP2	HGNC:12024	ENSG00000124490	P16562	Cysteine-rich secretory protein 2	clinvar
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	clinvar
PCNT	HGNC:16068	ENSG00000160299	O95613	Pericentrin	clinvar
SWT1	HGNC:16785	ENSG00000116668	Q5T5J6	Transcriptional protein SWT1	clinvar
CDH17	HGNC:1756	ENSG00000079112	Q12864	Cadherin-17	clinvar
CEP83	HGNC:17966	ENSG00000173588	Q9Y592	Centrosomal protein of 83 kDa	clinvar
ATP6V1C2	HGNC:18264	ENSG00000143882	Q8NEY4	V-type proton ATPase subunit C 2	clinvar
HIC2	HGNC:18595	ENSG00000169635	Q96JB3	Hypermethylated in cancer 2 protein	clinvar
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	clinvar
SDK1	HGNC:19307	ENSG00000146555	Q7Z5N4	Protein sidekick-1	clinvar
GALNT11	HGNC:19875	ENSG00000178234	Q8NCW6	Polypeptide N-acetylgalactosaminyltransferase 11	clinvar
CLDN18	HGNC:2039	ENSG00000066405	P56856	Claudin-18	clinvar
LINGO2	HGNC:21207	ENSG00000174482	Q7L985	Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
AP5Z1	HGNC:22197	ENSG00000242802	O43299	AP-5 complex subunit zeta-1	clinvar
SLC29A4	HGNC:23097	ENSG00000164638	Q7RTT9	Equilibrative nucleoside transporter 4	clinvar
AGAP6	HGNC:23466	ENSG00000204149	Q5VW22	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6	clinvar
TMEM132C	HGNC:25436	ENSG00000181234	Q8N3T6	Transmembrane protein 132C	clinvar
INO80D	HGNC:25997	ENSG00000114933	Q53TQ3	INO80 complex subunit D	clinvar
CCDC102B	HGNC:26295	ENSG00000150636	Q68D86	Coiled-coil domain-containing protein 102B	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar
L3MBTL4	HGNC:26677	ENSG00000154655	Q8NA19	Lethal(3)malignant brain tumor-like protein 4	clinvar
OTOGL	HGNC:26901	ENSG00000165899	Q3ZCN5	Otogelin-like protein	clinvar
C4orf46	HGNC:27320	ENSG00000205208	Q504U0	Renal cancer differentiation gene 1 protein	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
C1orf174	HGNC:27915	ENSG00000198912	Q8IYL3	UPF0688 protein C1orf174	clinvar
CASC15	HGNC:28245	ENSG00000272168		cancer susceptibility 15	clinvar
DGCR2	HGNC:2845	ENSG00000070413	P98153	Integral membrane protein DGCR2/IDD	clinvar
DNAH12	HGNC:2943	ENSG00000174844	Q6ZR08	Dynein axonemal heavy chain 12	clinvar
MMD2	HGNC:30133	ENSG00000136297	Q8IY49	Monocyte to macrophage differentiation factor 2	clinvar
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	clinvar
C2CD4B	HGNC:33628	ENSG00000205502	A6NLJ0	C2 calcium-dependent domain-containing protein 4B	clinvar
AHNAK	HGNC:347	ENSG00000124942	Q09666	Neuroblast differentiation-associated protein AHNAK	clinvar
ETFDH	HGNC:3483	ENSG00000171503	Q16134	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	clinvar
CMC4	HGNC:35428	ENSG00000182712	P56277	Cx9C motif-containing protein 4	clinvar
FHIT	HGNC:3701	ENSG00000189283	P49789	Bis(5’-adenosyl)-triphosphatase	clinvar
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	clinvar
GUCA1C	HGNC:4680	ENSG00000138472	O95843	Guanylyl cyclase-activating protein 3	clinvar
CTXND1	HGNC:50507	ENSG00000259417	A0A1B0GTU2	Cortexin domain-containing 1 protein	clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar
APPBP2	HGNC:622	ENSG00000062725	Q92624	Amyloid protein-binding protein 2	clinvar
A2M	HGNC:7	ENSG00000175899	P01023	Alpha-2-macroglobulin	clinvar
ABCF1	HGNC:70	ENSG00000204574	Q8NE71	ATP-binding cassette sub-family F member 1	clinvar
MTX2	HGNC:7506	ENSG00000128654	O75431	Metaxin-2	clinvar
ATIC	HGNC:794	ENSG00000138363	P31939	Bifunctional purine biosynthesis protein ATIC	clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RHCE	Blood group Rh(CE) polypeptide	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
SLC25A13	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.
SLC6A6	Sodium- and chloride-dependent taurine transporter	Mediates sodium- and chloride-dependent transport of taurine.
CRISP2	Cysteine-rich secretory protein 2	May regulate some ion channels’ activity and thereby regulate calcium fluxes during sperm capacitation.
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
PCNT	Pericentrin	Integral component of the filamentous matrix of the centrosome involved in the initial establishment of organized microtubule arrays in both mitosis and meiosis.
CDH17	Cadherin-17	Cadherins are calcium-dependent cell adhesion proteins.
CEP83	Centrosomal protein of 83 kDa	Component of the distal appendage region of the centriole involved in the initiation of primary cilium assembly.
ATP6V1C2	V-type proton ATPase subunit C 2	Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
HIC2	Hypermethylated in cancer 2 protein	Transcriptional repressor.
CFTR	Cystic fibrosis transmembrane conductance regulator	Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.
SDK1	Protein sidekick-1	Adhesion molecule that promotes lamina-specific synaptic connections in the retina.
GALNT11	Polypeptide N-acetylgalactosaminyltransferase 11	Polypeptide N-acetylgalactosaminyltransferase that catalyzes the initiation of protein O-linked glycosylation and is involved in left/right asymmetry by mediating O-glycosylation of NOTCH1.
CLDN18	Claudin-18	Involved in alveolar fluid homeostasis via regulation of alveolar epithelial tight junction composition and therefore ion transport and solute permeability, potentially via downstream regulation of the actin cytoskeleton organization and b…
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
AP5Z1	AP-5 complex subunit zeta-1	As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.
SLC29A4	Equilibrative nucleoside transporter 4	Electrogenic voltage-dependent transporter that mediates the transport of a variety of endogenous bioactive amines, cationic xenobiotics and drugs.
AGAP6	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6	Putative GTPase-activating protein.
INO80D	INO80 complex subunit D	Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
CCDC102B	Coiled-coil domain-containing protein 102B	During interphase, forms fibers at the proximal ends of centrioles to maintain centrosome cohesion.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.
L3MBTL4	Lethal(3)malignant brain tumor-like protein 4	Putative Polycomb group (PcG) protein.
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
DGCR2	Integral membrane protein DGCR2/IDD	Putative adhesion receptor, that could be involved in cell-cell or cell-matrix interactions required for normal cell differentiation and migration.
DNAH12	Dynein axonemal heavy chain 12	Involved in spermiogenesis.
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.
C2CD4B	C2 calcium-dependent domain-containing protein 4B	May be involved in inflammatory process.
AHNAK	Neuroblast differentiation-associated protein AHNAK	May be required for neuronal cell differentiation.
ETFDH	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	Accepts electrons from ETF and reduces ubiquinone.
FHIT	Bis(5’-adenosyl)-triphosphatase	Possesses dinucleoside triphosphate hydrolase activity.
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
GUCA1C	Guanylyl cyclase-activating protein 3	Stimulates guanylyl cyclase 1 (GC1) and GC2 when free calcium ions concentration is low and inhibits guanylyl cyclases when free calcium ions concentration is elevated.
APPBP2	Amyloid protein-binding protein 2	Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to…
A2M	Alpha-2-macroglobulin	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
ABCF1	ATP-binding cassette sub-family F member 1	Isoform 2 is required for efficient Cap- and IRES-mediated mRNA translation initiation.
MTX2	Metaxin-2	Involved in transport of proteins into the mitochondrion.
ATIC	Bifunctional purine biosynthesis protein ATIC	Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 13 · Difficult: 6 · Unknown: 30 · Druggable fraction: 0.27

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	4	6.3×	0.029
Complement	1	5.5×	0.670
Other/Unknown	30	1.1×	0.718
Antibody/Immunoglobulin	2	1.2×	0.790
Kinase	2	1.1×	0.790
Enzyme (other)	4	1.0×	0.790
Scaffold/PPI	2	0.7×	0.860
Transcription factor	4	0.7×	0.860

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RHCE	Other/Unknown	no		RhesusRHD, NH4_transpt_AmtB-like_dom, Ammonium/urea_transptr
SLC25A13	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair
SLC6A6	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_taurine, SNS_sf
CRISP2	Other/Unknown	no		CRISP-related, ShKT_dom, Cysteine_rich_secretory
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
PCNT	Other/Unknown	no		PACT_domain, AKAP9/Pericentrin
SWT1	Other/Unknown	no		PIN_dom, PIN-like_dom_sf, SWT1_Regulator
CDH17	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
CEP83	Other/Unknown	no		Centro_Cilium_Assembly
ATP6V1C2	Other/Unknown	no		ATPase_V1-cplx_csu, Vac_ATP_synth_c_sf
HIC2	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
CFTR	Transporter	yes	2.7.4.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, CFTR/ABCC7
SDK1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
GALNT11	Enzyme (other)	yes	2.4.1.41	Ricin_B_lectin, Glyco_trans_2-like, Nucleotide-diphossugar_trans
CLDN18	Other/Unknown	no		Claudin18, PMP22/EMP/MP20/Claudin, Claudin
LINGO2	Antibody/Immunoglobulin	yes		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
AP5Z1	Other/Unknown	no		ARM-like, AP5Z1, AP5Z1_ARM
SLC29A4	Transporter	yes		Eqnu_transpt, MFS_trans_sf
AGAP6	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt
TMEM132C	Other/Unknown	no		TMEM132, TMEM132_N, TMEM132_C
INO80D	Transcription factor	no		Znf_KANL2-like
CCDC102B	Other/Unknown	no
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom
L3MBTL4	Transcription factor	no		SAM, Znf_C2H2C, Mbt
OTOGL	Other/Unknown	no		VWF_dom, VWF_type-D, TIL_dom
C4orf46	Other/Unknown	no		RCDG1
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
C1orf174	Other/Unknown	no		UPF0688
CASC15	Other/Unknown	no
DGCR2	Other/Unknown	no		VWF_dom, C-type_lectin-like, LDrepeatLR_classA_rpt
DNAH12	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dhc_linker
MMD2	Other/Unknown	no		AdipoR/HlyIII-related
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
C2CD4B	Other/Unknown	no		C2_dom, C2_domain_sf, C2_Ca-dependent_4
AHNAK	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
ETFDH	Enzyme (other)	yes	1.5.5.1	ETF-QO/FixX_C, 4Fe4S_Fe-S-bd, FAD/NAD-bd_sf
CMC4	Other/Unknown	no		Cys_alpha_HP_mot_SF, CMC4
FHIT	Enzyme (other)	yes	3.6.1.29	HIT-like, Histidine_triad_CS, HIT-like_sf
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
GUCA1C	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CTXND1	Other/Unknown	no		Cortexin
CCDST	Other/Unknown	no
APPBP2	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, APPBP2
A2M	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
ABCF1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC_transporter-like_CS
MTX2	Other/Unknown	no		Sam37/metaxin_N, Metaxin_GST, Glutathione-S-Trfase_C_sf
ATIC	Enzyme (other)	yes	2.1.2.3	PurH-like, MGS-like_dom, Cytidine_deaminase-like
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

Expression context

Cohort genes with no expression data: 0.

42 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)	49
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	7
secondary oocyte	5
calcaneal tendon	5
male germ line stem cell (sensu Vertebrata) in testis	4
cortical plate	4
buccal mucosa cell	4
gastrocnemius	3
hindlimb stylopod muscle	3
oocyte	3
body of pancreas	3
pancreas	3
tendon of biceps brachii	3
primordial germ cell in gonad	3
apex of heart	3
bone marrow	2
sperm	2
right uterine tube	2
lower esophagus mucosa	2
gall bladder	2
decidua	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHCE	169	broad	marker	trabecular bone tissue, bone marrow, male germ line stem cell (sensu Vertebrata) in testis
SLC25A13	283	ubiquitous	marker	right lobe of liver, liver, secondary oocyte
SLC6A6	265	ubiquitous	marker	mucosa of paranasal sinus, palpebral conjunctiva, olfactory segment of nasal mucosa
CRISP2	163	tissue_specific	marker	sperm, male germ cell, adult organism
ZEB2	290	ubiquitous	marker	cortical plate, sural nerve, monocyte
PCNT	283	ubiquitous	marker	gastrocnemius, body of tongue, hindlimb stylopod muscle
SWT1	214	ubiquitous	yes	sperm, secondary oocyte, calcaneal tendon
CDH17	153	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, ileal mucosa
CEP83	233	ubiquitous	marker	right uterine tube, calcaneal tendon, sural nerve
ATP6V1C2	181	broad	marker	skin of abdomen, skin of leg, lower esophagus mucosa
HIC2	260	ubiquitous	marker	secondary oocyte, oocyte, amniotic fluid
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas
SDK1	183	broad	marker	popliteal artery, decidua, tibial artery
GALNT11	286	ubiquitous	marker	choroid plexus epithelium, renal medulla, nephron tubule
CLDN18	173	tissue_specific	marker	pylorus, lower lobe of lung, cardia of stomach
LINGO2	157	broad	marker	secondary oocyte, oocyte, endothelial cell
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
AP5Z1	233	ubiquitous	marker	granulocyte, tendon of biceps brachii, buccal mucosa cell
SLC29A4	187	broad	marker	buccal mucosa cell, islet of Langerhans, cortical plate
AGAP6	132		yes	pituitary gland, adenohypophysis, right hemisphere of cerebellum
TMEM132C	199	broad	marker	decidua, buccal mucosa cell, upper arm skin
INO80D	134	ubiquitous	yes	bone marrow cell, bone marrow, sural nerve
CCDC102B	190	ubiquitous	marker	sural nerve, calcaneal tendon, gall bladder
AIFM3	180	tissue_specific	marker	mucosa of transverse colon, right frontal lobe, right hemisphere of cerebellum
L3MBTL4	193	broad	marker	oviduct epithelium, kidney epithelium, sural nerve
OTOGL	152	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right atrium auricular region, cardiac atrium
C4orf46	206	ubiquitous	yes	buccal mucosa cell, primordial germ cell in gonad, ganglionic eminence
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
C1orf174	281	ubiquitous	marker	oocyte, secondary oocyte, gingival epithelium
CASC15	223	ubiquitous	marker	ganglionic eminence, ventricular zone, sural nerve

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
CDH17	4,513
RET	4,203
AHNAK	4,006
ATIC	3,960
PCNT	3,934
COL3A1	3,629
ABCF1	3,470
AKT3	3,392
ZEB2	3,193

Intra-cohort edges

A	B	Sources
ABCF1	CFTR	intact
AHNAK	CFTR	intact
CCDC102B	L3MBTL4	string_interaction
CFTR	DES	intact
CFTR	PCNT	intact
CFTR	SLC25A13	intact
CFTR	SLC6A6	intact
EDN3	RET	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 25 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFTR	P13569	58
SLC6A6	P31641	45
RET	P07949	34
A2M	P01023	13
COL3A1	P02461	11
FHIT	P49789	9
RHCE	P18577	8
AIFM3	Q96NN9	7
APPBP2	Q92624	6
ATIC	P31939	5
CDH17	Q12864	3
CLDN18	P56856	3
AHNAK	Q09666	3
CMC4	P56277	3
AKT3	Q9Y243	2
SLC25A13	Q9UJS0	1
CRISP2	P16562	1
ZEB2	O60315	1
HIC2	Q96JB3	1
EDN3	P14138	1
GUCA1C	O95843	1
ABCF1	Q8NE71	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ETFDH	Q16134	93.60
MTX2	O75431	92.54
MMD2	Q8IY49	87.62
ATP6V1C2	Q8NEY4	86.29
GALNT11	Q8NCW6	85.38
AP5Z1	O43299	85.32
LINGO2	Q7L985	85.02
CEP83	Q9Y592	81.90
C4orf46	Q504U0	80.81
CTXND1	A0A1B0GTU2	80.09
DES	P17661	77.73
CCDC102B	Q68D86	76.95
L3MBTL4	Q8NA19	75.26
SLC29A4	Q7RTT9	74.78
SDK1	Q7Z5N4	72.92
OTOGL	Q3ZCN5	72.19
TMEM132C	Q8N3T6	69.84
DGCR2	P98153	63.74
AGAP6	Q5VW22	63.73
C1orf174	Q8IYL3	61.92
SWT1	Q5T5J6	60.89
C2CD4B	A6NLJ0	60.81
INO80D	Q53TQ3	52.25
PCNT	O95613
DNAH12	Q6ZR08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 185. Enrichment computed across 49 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial protein import	3	18.7×	0.099	SLC25A13, CMC4, MTX2
Chaperone Mediated Autophagy	2	36.8×	0.122	PCNT, CFTR
SDK interactions	1	211.5×	0.138	SDK1
Rhesus blood group biosynthesis	1	211.5×	0.138	RHCE
Late endosomal microautophagy	2	24.2×	0.138	PCNT, CFTR
Cell-cell junction organization	2	18.4×	0.138	CDH17, SDK1
Aggrephagy	2	18.4×	0.138	PCNT, CFTR
RHO GTPases regulate CFTR trafficking	1	141.0×	0.141	CFTR
AKT-mediated inactivation of FOXO1A	1	105.7×	0.141	AKT3
Developmental Lineage of Pancreatic Ductal Cells	2	16.9×	0.141	CFTR, COL3A1
Protein localization	2	14.1×	0.141	SLC25A13, MTX2
Cell junction organization	2	13.9×	0.141	CDH17, SDK1
Transcriptional and post-translational regulation of MITF-M expression and activity	2	13.2×	0.141	EDN3, AKT3
Inhibition of TSC complex formation by AKT (PKB)	1	84.6×	0.152	AKT3
G-protein beta:gamma signalling	1	70.5×	0.152	AKT3
R-HSA-140837	1	52.9×	0.152	A2M
RUNX2 regulates genes involved in cell migration	1	52.9×	0.152	AKT3
HDL assembly	1	52.9×	0.152	A2M
Malate-aspartate shuttle	1	47.0×	0.152	SLC25A13
AKT phosphorylates targets in the nucleus	1	42.3×	0.152	AKT3
Formation of the posterior neural plate	1	42.3×	0.152	ZEB2
Regulation of FXIIa and plasma kallikrein activity	1	42.3×	0.152	A2M
Purine ribonucleoside monophosphate biosynthesis	1	38.5×	0.152	ATIC
Aspartate and asparagine metabolism	1	38.5×	0.152	SLC25A13
Regulation of CDH11 gene transcription	1	38.5×	0.152	ZEB2
Formation of the anterior neural plate	1	38.5×	0.152	ZEB2
R-HSA-140877	1	35.2×	0.152	A2M
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	35.2×	0.152	SLC29A4
Regulation of localization of FOXO transcription factors	1	35.2×	0.152	AKT3
Positive Regulation of CDH1 Gene Transcription	1	35.2×	0.152	ZEB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 39 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of cell size	2	66.5×	0.051	AKT3, RET
mitochondrial transport	2	61.7×	0.051	SLC25A13, MTX2
neural crest cell migration	3	25.9×	0.051	ZEB2, EDN3, RET
oligopeptide transport	1	432.1×	0.065	CDH17
diadenosine triphosphate catabolic process	1	432.1×	0.065	FHIT
vibrational conductance of sound to the inner ear	1	432.1×	0.065	OTOGL
Notch signaling involved in heart development	1	432.1×	0.065	GALNT11
mammillary axonal complex development	1	432.1×	0.065	ZEB2
obsolete organic acid transmembrane transport	1	432.1×	0.065	SLC29A4
positive regulation of myofibroblast contraction	1	432.1×	0.065	ZEB2
regulation of blood-brain barrier permeability	1	432.1×	0.065	ZEB2
embryonic epithelial tube formation	1	216.1×	0.065	RET
negative regulation of complement activation, lectin pathway	1	216.1×	0.065	A2M
posterior midgut development	1	216.1×	0.065	RET
positive regulation of integrin activation by cell surface receptor linked signal transduction	1	216.1×	0.065	CDH17
L-arabinose metabolic process	1	216.1×	0.065	OTOGL
epinephrine uptake	1	216.1×	0.065	SLC29A4
positive regulation of lens fiber cell differentiation	1	216.1×	0.065	ZEB2
regulation of melanosome organization	1	216.1×	0.065	ZEB2
regulation of myofibroblast cell apoptotic process	1	216.1×	0.065	ZEB2
regulation of vascular permeability involved in acute inflammatory response	1	144.0×	0.065	C2CD4B
purine nucleotide metabolic process	1	144.0×	0.065	FHIT
transforming growth factor beta1 production	1	144.0×	0.065	COL3A1
limb joint morphogenesis	1	144.0×	0.065	COL3A1
dihydrofolate metabolic process	1	144.0×	0.065	ATIC
regulation of developmental pigmentation	1	144.0×	0.065	EDN3
intracellular pH elevation	1	144.0×	0.065	CFTR
histamine transport	1	144.0×	0.065	SLC29A4
positive regulation of metanephric glomerulus development	1	144.0×	0.065	RET
melanocyte migration	1	144.0×	0.065	ZEB2

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 6 · Phased (≥1): 6 · Undrugged: 43

Druggability breadth: 17 of 49 evidence-associated genes (35%) 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
CFTR	IVACAFTOR
AKT3	CAPIVASERTIB
ATIC	PEMETREXED
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
AKT3	18	4
CFTR	14	4
ATIC	3	4
SLC6A6	1	3
FHIT	1	3
RHCE	0	0
SLC25A13	0	0
CRISP2	0	0
ZEB2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
CAPIVASERTIB	4	AKT3, RET
MIDOSTAURIN	4	AKT3, RET
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
AKT3	660	Binding:644, Functional:16
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1
ATIC	95	Binding:95
FHIT	21	Binding:19, ADMET:2
SLC29A4	15	ADMET:13, Binding:2
L3MBTL4	7	Binding:7
ABCF1	7	Binding:7
AP5Z1	6	Binding:6
SLC6A6	5	Binding:4, Functional:1
AHNAK	2	Binding:2
SLC25A13	1	Binding:1
DNAH12	1	Binding:1
A2M	1	Binding:1
MTX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase
GALNT11	2.4.1.41	polypeptide N-acetylgalactosaminyltransferase
ETFDH	1.5.5.1	electron-transferring-flavoprotein dehydrogenase
FHIT	3.6.1.29	bis(5’-adenosyl)-triphosphatase
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
ATIC	2.1.2.3, 3.5.4.10	phosphoribosylaminoimidazolecarboxamide formyltransferase, IMP cyclohydrolase
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CFTR	520
AKT3	660
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 47; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CFTR	1

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)
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
CAPIVASERTIB	4	AKT3, RET
MIDOSTAURIN	4	AKT3, RET
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	CFTR, AKT3, ATIC, RET
B	Phased (≥1) drug, not yet approved	2	SLC6A6, FHIT
C	Druggable family + PDB, no drug	3	SLC25A13, A2M, ABCF1
D	Druggable family + AlphaFold only, no drug	5	SDK1, GALNT11, LINGO2, SLC29A4, ETFDH
E	Difficult family or no structure, no drug	35	RHCE, CRISP2, ZEB2, PCNT, SWT1, CDH17, CEP83, ATP6V1C2, HIC2, CLDN18 (+25 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RHCE	0	—
SLC25A13	1	—
CRISP2	0	—
ZEB2	0	—
PCNT	0	—
SWT1	0	—
CDH17	0	—
CEP83	0	—
ATP6V1C2	0	—
HIC2	0	—
SDK1	0	—
GALNT11	0	—
CLDN18	0	—
LINGO2	0	—
COL3A1	0	—
AP5Z1	6	—
SLC29A4	15	—
AGAP6	0	—
TMEM132C	0	—
INO80D	0	—
CCDC102B	0	—
AIFM3	0	—
L3MBTL4	7	—
OTOGL	0	—
C4orf46	0	—
DES	0	—
C1orf174	0	—
CASC15	0	—
DGCR2	0	—
DNAH12	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07470892	Not specified	NOT_YET_RECRUITING	Preoperative Fish Oil PN and Prognosis After Constipation Surgery
NCT04340856	Not specified	COMPLETED	Retrospective, Uncontrolled Cohort Study on the Therapy of Chronic Megalon