Gastroesophageal reflux disease

disease

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Also known as acid refluxgastroesophageal refluxgastroesophageal reflux, paediatricgerGERD

Summary

Gastroesophageal reflux disease (MONDO:0007186) is a disease with 75 cohort genes (510 GWAS associations across 77 studies) and 777 clinical trials. The dominant Reactome pathway is Butyrophilin (BTN) family interactions (3 cohort genes). Top therapeutic interventions include esomeprazole, rabeprazole, and pantoprazole.

At a glance

Cohort genes: 75
GWAS associations: 510
Clinical trials: 777

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	gastroesophageal reflux disease
Mondo ID	MONDO:0007186
EFO	EFO:0003948
MeSH	D005764
OMIM	109350
DOID	DOID:8534
ICD-11	1391387859
NCIT	C26781
SNOMED CT	235595009
UMLS	C0017168
MedGen	6553
Is cancer (heuristic)	no

Also known as: acid reflux · gastroesophageal reflux · gastroesophageal reflux disease · gastroesophageal reflux, paediatric · ger · GERD

Data availability: 510 GWAS associations (77 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › upper digestive tract disorder › esophageal disorder › gastroesophageal reflux disease

Subtypes (1): duodenogastric reflux

Genetics & variants

GWAS landscape

510 GWAS associations across 77 studies. Top hits map to 21 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2070729	7e-28	IRF1, CARINH	?	1.01
chr9:96580113	2e-22		A	0.05
rs9673356	9e-20	AKTIP - RPGRIP1L	A	0.04
rs1977199	8e-19	BTN2A1	?
rs7752448	1e-18	ZSCAN31	?
rs3118368	3e-18	LINC01623 - ZNF90P2	?
chr9:128660676	4e-18		G	0.04
chr9:96586175	6e-18		G	0.04
rs3115631	1e-17	POLR1HASP, POLR1HASP	?
rs13212562	1e-17	VN1R10P - ZNF204P	?
rs2523599	1e-17	HLA-C - USP8P1	?
rs1542726	3e-17	KRT18P51 - HHIP-AS1	?	1.01
rs9393711	6e-17	BTN3A2	?
rs2442749	1e-16	MICA-AS1	?
rs11762636	2e-16	MAD1L1	C	0.05
rs6934329	5e-16	MIR3143 - RPL10P2	?
rs1233578	3e-15	RPSAP2 - NOP56P1	?
rs1980493	5e-15	BTNL2, TSBP1-AS1	?
rs10404696	7e-15	CRTC1	G	0.04
rs200965	1e-14	RNU7-26P - OR2B2	?
rs4766578	1e-14	ATXN2	T	0.03
chr6:34603350	1e-14		G	0.04
rs13135092	1e-14	SLC39A8	?	1.02
rs13107325	2e-14	SLC39A8	C	0.07
rs9372625	3e-14	MMS22L - MIR2113	G	0.04
rs13404344	3e-14	LINC00299	?	0.99
rs57882762	4e-14	PHF2 - MIR4291	T	0.04
chr16:53579858	5e-14		T	0.04
rs2891698	5e-14	KLHL26 - CRTC1	G	0.03
chr6:31359557	6e-14		T	0.04

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90476047	Verma A	2024	175,991	236,737	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90000514	Ong JS	2021	129,080	473,524	Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.
GCST90432132	Jiang Y	2023	116,382	213,325	A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders.
GCST90475320	Verma A	2024	107,942	207,726	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST011500	Wu Y	2021	90,175	366,152	GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression.
GCST90475321	Verma A	2024	86,135	229,533	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST008832	An J	2019	80,265	305,011	Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.
GCST90454172	Jiang M	2023	77,721	693,729	Genetic and observational associations of lung function with gastrointestinal tract diseases: pleiotropic and mendelian randomization analysis.
GCST90454176	Jiang M	2023	77,721	693,729	Genetic and observational associations of lung function with gastrointestinal tract diseases: pleiotropic and mendelian randomization analysis.
GCST90454180	Jiang M	2023	77,721	693,729	Genetic and observational associations of lung function with gastrointestinal tract diseases: pleiotropic and mendelian randomization analysis.

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	46

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	25
unknown	11
intergenic_variant	10
missense_variant	3
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2070729	5	132484229	C>A,G,T	0.05	intron_variant	IRF1, CARINH	7e-28	Tier 4: intronic/intergenic
chr9:96580113				0.4			2e-22	Tier 4: intronic/intergenic
rs9673356	16	53530276	A>C,G	0.344	intergenic_variant	AKTIP - RPGRIP1L	9e-20	Tier 4: intronic/intergenic
rs1977199	6	26466161	G>A,C	0.05	intron_variant	BTN2A1	8e-19	Tier 4: intronic/intergenic
rs7752448	6	28333322	A>G	0.05	intron_variant	ZSCAN31	1e-18	Tier 4: intronic/intergenic
rs3118368	6	28869332	T>A,C	0.05	intergenic_variant	LINC01623 - ZNF90P2	3e-18	Tier 4: intronic/intergenic
chr9:128660676				0.354			4e-18	Tier 4: intronic/intergenic
chr9:96586175				0.435			6e-18	Tier 4: intronic/intergenic
rs3115631	6	30018547	T>A	0.05	intron_variant	POLR1HASP, POLR1HASP	1e-17	Tier 4: intronic/intergenic
rs13212562	6	27332531	A>G	0.05	intergenic_variant	VN1R10P - ZNF204P	1e-17	Tier 4: intronic/intergenic
rs2523599	6	31273315	C>A,G,T	0.05	intron_variant	HLA-C - USP8P1	1e-17	Tier 4: intronic/intergenic
rs1542726	4	144594617	A>C	0.05	intron_variant	KRT18P51 - HHIP-AS1	3e-17	Tier 4: intronic/intergenic
rs9393711	6	26370431	C>A,T	0.05	missense_variant	BTN3A2	6e-17	Tier 1: coding
rs2442749	6	31384263	T>A,C,G	0.05	intron_variant	MICA-AS1	1e-16	Tier 4: intronic/intergenic
rs11762636	7	2021476	C>A,T	0.18	intron_variant	MAD1L1	2e-16	Tier 4: intronic/intergenic
rs6934329	6	27190254	A>G	0.05	intron_variant	MIR3143 - RPL10P2	5e-16	Tier 4: intronic/intergenic
rs1233578	6	28744470	A>G,T	0.05	intron_variant	RPSAP2 - NOP56P1	3e-15	Tier 4: intronic/intergenic
rs1980493	6	32395438	T>A,C,G	0.05	intron_variant	BTNL2, TSBP1-AS1	5e-15	Tier 4: intronic/intergenic
rs10404696	19	18693485	G>T	0.479	intron_variant	CRTC1	7e-15	Tier 4: intronic/intergenic
rs200965	6	27898606	G>A	0.05	intergenic_variant	RNU7-26P - OR2B2	1e-14	Tier 4: intronic/intergenic
rs4766578	12	111466567	T>A	0.495	intron_variant	ATXN2	1e-14	Tier 4: intronic/intergenic
chr6:34603350				0.189			1e-14	Tier 4: intronic/intergenic
rs13135092	4	102276925	A>G	0.05	intron_variant	SLC39A8	1e-14	Tier 4: intronic/intergenic
rs13107325	4	102267552	C>A,T	0.07	missense_variant	SLC39A8	2e-14	Tier 1: coding
rs9372625	6	97896155	G>A	0.38	intron_variant	MMS22L - MIR2113	3e-14	Tier 4: intronic/intergenic
rs13404344	2	8338203	C>A,G,T	0.05	intergenic_variant	LINC00299	3e-14	Tier 4: intronic/intergenic
rs57882762	9	93818543	T>A,C,G	0.413	intron_variant	PHF2 - MIR4291	4e-14	Tier 4: intronic/intergenic
chr16:53579858				0.309			5e-14	Tier 4: intronic/intergenic
rs2891698	19	18677171	G>A,C	0.477	intergenic_variant	KLHL26 - CRTC1	5e-14	Tier 4: intronic/intergenic
chr6:31359557							6e-14	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 41 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
SUOX	Orphanet:99731	Isolated sulfite oxidase deficiency
TRAF3	Orphanet:1930	Herpes simplex virus encephalitis
CNTNAP2	Orphanet:163681	CNTNAP2-related developmental and epileptic encephalopathy
FOXP2	Orphanet:209908	Isolated childhood apraxia of speech
FOXP2	Orphanet:251061	7q31 microdeletion syndrome
ADAMTS17	Orphanet:3449	Weill-Marchesani syndrome
ADAMTS17	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
SLC39A8	Orphanet:468699	SLC39A8-CDG
VCAN	Orphanet:898	Wagner disease
ANO10	Orphanet:284289	Adult-onset autosomal recessive cerebellar ataxia
DCC	Orphanet:238722	Familial congenital mirror movements
DCC	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
DCC	Orphanet:478	Kallmann syndrome
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
DPYD	Orphanet:1675	Dihydropyrimidine dehydrogenase deficiency
DPYD	Orphanet:293948	1p21.3 microdeletion syndrome
EIF2B2	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B2	Orphanet:157716	Late infantile CACH syndrome
EIF2B2	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B2	Orphanet:99853	Ovarioleukodystrophy
EIF2B2	Orphanet:99854	Cree leukoencephalopathy
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
FOXP1	Orphanet:391372	FOXP1 Syndrome
FOXP1	Orphanet:52417	MALT lymphoma
FOXP1	Orphanet:585877	B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
HIVEP2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
HLA-B	Orphanet:117	Behçet disease
HLA-B	Orphanet:275798	Pulmonary arterial hypertension associated with connective tissue disease
HLA-B	Orphanet:29207	Reactive arthritis
HLA-B	Orphanet:3287	Takayasu arteritis
HLA-B	Orphanet:36426	Stevens-Johnson syndrome
HLA-B	Orphanet:397	Giant cell arteritis
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia
AFF3	Orphanet:632603	Mesomelic dysplasia-digital anomalies-intellectual disability syndrome

Cohort genes → proteins

75 cohort genes, 67 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU4-1	HGNC:10192	ENSG00000200795		RNA, U4 small nuclear 1	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
SLCO3A1	HGNC:10952	ENSG00000176463	Q9UIG8	Solute carrier organic anion transporter family member 3A1	gwas
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gwas
BTN1A1	HGNC:1135	ENSG00000124557	Q13410	Butyrophilin subfamily 1 member A1	gwas
BTN2A1	HGNC:1136	ENSG00000112763	Q7KYR7	Butyrophilin subfamily 2 member A1	gwas
BTN3A3	HGNC:1140	ENSG00000111801	O00478	Butyrophilin subfamily 3 member A3	gwas
STK24	HGNC:11403	ENSG00000102572	Q9Y6E0	Serine/threonine-protein kinase 24	gwas
SUOX	HGNC:11460	ENSG00000139531	P51687	Sulfite oxidase, mitochondrial	gwas
TRAF3	HGNC:12033	ENSG00000131323	Q13114	TNF receptor-associated factor 3	gwas
EPCIP	HGNC:1305	ENSG00000205929	Q9NYP8	Exosomal polycystin-1-interacting protein	gwas
TMEM59L	HGNC:13237	ENSG00000105696	Q9UK28	Transmembrane protein 59-like	gwas
PGPEP1	HGNC:13568	ENSG00000130517	Q9NXJ5	Pyroglutamyl-peptidase 1	gwas
CA10	HGNC:1369	ENSG00000154975	Q9NS85	Carbonic anhydrase-related protein 10	gwas
CNTNAP2	HGNC:13830	ENSG00000174469	Q9UHC6	Contactin-associated protein-like 2	gwas
FOXP2	HGNC:13875	ENSG00000128573	O15409	Forkhead box protein P2	gwas
CELF4	HGNC:14015	ENSG00000101489	Q9BZC1	CUGBP Elav-like family member 4	gwas
CSMD1	HGNC:14026	ENSG00000183117	Q96PZ7	CUB and sushi domain-containing protein 1	gwas
CCKBR	HGNC:1571	ENSG00000110148	P32239	Gastrin/cholecystokinin type B receptor	gwas
RERG	HGNC:15980	ENSG00000134533	Q96A58	Ras-related and estrogen-regulated growth inhibitor	gwas
NAV3	HGNC:15998	ENSG00000067798	Q8IVL0	Neuron navigator 3	gwas
CRTC1	HGNC:16062	ENSG00000105662	Q6UUV9	CREB-regulated transcription coactivator 1	gwas
MAML3	HGNC:16272	ENSG00000196782	Q96JK9	Mastermind-like protein 3	gwas
MRM2	HGNC:16352	ENSG00000122687	Q9UI43	rRNA methyltransferase 2, mitochondrial	gwas
SORCS3	HGNC:16699	ENSG00000156395	Q9UPU3	VPS10 domain-containing receptor SorCS3	gwas
NEBL	HGNC:16932	ENSG00000078114	O76041	Nebulette	gwas
ADAMTS17	HGNC:17109	ENSG00000140470	Q8TE56	A disintegrin and metalloproteinase with thrombospondin motifs 17	gwas
LSM4	HGNC:17259	ENSG00000130520	Q9Y4Z0	U6 snRNA-associated Sm-like protein LSm4	gwas
NEGR1	HGNC:17302	ENSG00000172260	Q7Z3B1	Neuronal growth regulator 1	gwas
HCG11	HGNC:17707	ENSG00000228223		HLA complex group 11	gwas
CDK2	HGNC:1771	ENSG00000123374	P24941	Cyclin-dependent kinase 2	gwas
YLPM1	HGNC:17798	ENSG00000119596	P49750	YLP motif-containing protein 1	gwas
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	gwas
SDK1	HGNC:19307	ENSG00000146555	Q7Z5N4	Protein sidekick-1	gwas
UNC79	HGNC:19966	ENSG00000133958	Q9P2D8	Protein unc-79 homolog	gwas
SLC39A8	HGNC:20862	ENSG00000138821	Q9C0K1	Metal cation symporter ZIP8	gwas
BLTP3A	HGNC:21216	ENSG00000065060	Q6BDS2	Bridge-like lipid transfer protein family member 3A	gwas
CNGA4	HGNC:2152	ENSG00000132259	Q8IV77	Cyclic nucleotide-gated channel alpha-4	gwas
TAFA5	HGNC:21592	ENSG00000219438	Q7Z5A7	Chemokine-like protein TAFA-5	gwas
ADARB1	HGNC:226	ENSG00000197381	P78563	Double-stranded RNA-specific editase 1	gwas
HAPLN1	HGNC:2380	ENSG00000145681	P10915	Hyaluronan and proteoglycan link protein 1	gwas
COX8C	HGNC:24382	ENSG00000187581	Q7Z4L0	Cytochrome c oxidase subunit 8C, mitochondrial	gwas
VCAN	HGNC:2464	ENSG00000038427	P13611	Versican core protein	gwas
RBM43	HGNC:24790	ENSG00000184898	Q6ZSC3	RNA-binding protein 43	gwas
ANO10	HGNC:25519	ENSG00000160746	Q9NW15	Anoctamin-10	gwas
KLHL26	HGNC:25623	ENSG00000167487	Q53HC5	Kelch-like protein 26	gwas
REX1BD	HGNC:26098	ENSG00000006015	Q96EN9	Required for excision 1-B domain-containing protein	gwas
CRTC3	HGNC:26148	ENSG00000140577	Q6UUV7	CREB-regulated transcription coactivator 3	gwas
PROX2	HGNC:26715	ENSG00000119608	Q3B8N5	Prospero homeobox protein 2	gwas
DCC	HGNC:2701	ENSG00000187323	P43146	Netrin receptor DCC	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SLCO3A1	Solute carrier organic anion transporter family member 3A1	Putative organic anion antiporter with apparent broad substrate specificity.
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
BTN1A1	Butyrophilin subfamily 1 member A1	May function in the secretion of milk-fat droplets.
BTN3A3	Butyrophilin subfamily 3 member A3	Plays a role in T-cell responses in the adaptive immune response.
STK24	Serine/threonine-protein kinase 24	Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation.
SUOX	Sulfite oxidase, mitochondrial	Catalyzes the oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of sulfur-containing amino acids.
TRAF3	TNF receptor-associated factor 3	Cytoplasmic E3 ubiquitin ligase that regulates various signaling pathways, such as the NF-kappa-B, mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus controls a lot of biological processes in…
EPCIP	Exosomal polycystin-1-interacting protein	Likely to be involved with PKD1 in the detection, sequestration and exocytosis of senescent mitochondria.
TMEM59L	Transmembrane protein 59-like	Modulates the O-glycosylation and complex N-glycosylation steps occurring during the Golgi maturation of APP.
PGPEP1	Pyroglutamyl-peptidase 1	Removes 5-oxoproline from various penultimate amino acid residues except L-proline.
CA10	Carbonic anhydrase-related protein 10	Does not have a catalytic activity.
CNTNAP2	Contactin-associated protein-like 2	Required for gap junction formation.
FOXP2	Forkhead box protein P2	Transcriptional repressor that may play a role in the specification and differentiation of lung epithelium.
CELF4	CUGBP Elav-like family member 4	RNA-binding protein implicated in the regulation of pre-mRNA alternative splicing.
CSMD1	CUB and sushi domain-containing protein 1	Potential suppressor of squamous cell carcinomas.
CCKBR	Gastrin/cholecystokinin type B receptor	Receptor for the peptide hormones gastrin and cholecystokinin (CCK).
RERG	Ras-related and estrogen-regulated growth inhibitor	Binds GDP/GTP and possesses intrinsic GTPase activity.
NAV3	Neuron navigator 3	Is involved in microtubule cytoskeleton organization and plays a role in cell migration.
CRTC1	CREB-regulated transcription coactivator 1	Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites.
MAML3	Mastermind-like protein 3	Acts as a transcriptional coactivator for NOTCH proteins.
MRM2	rRNA methyltransferase 2, mitochondrial	S-adenosyl-L-methionine-dependent 2’-O-ribose methyltransferase that catalyzes the formation of 2’-O-methyluridine at position 1369 (Um1369) in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA), a universally conserved modific…
SORCS3	VPS10 domain-containing receptor SorCS3	Plays an important role in modulating synaptic transmission and plasticity in the hippocampus, probably by affecting the trafficking and localization ofAMPA-type glutamate receptors in the postsynaptic density.
NEBL	Nebulette	Binds to actin and plays an important role in the assembly of the Z-disk.
LSM4	U6 snRNA-associated Sm-like protein LSm4	Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
NEGR1	Neuronal growth regulator 1	May be involved in cell-adhesion.
CDK2	Cyclin-dependent kinase 2	Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis.
YLPM1	YLP motif-containing protein 1	Plays a role in the reduction of telomerase activity during differentiation of embryonic stem cells by binding to the core promoter of TERT and controlling its down-regulation.
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
SDK1	Protein sidekick-1	Adhesion molecule that promotes lamina-specific synaptic connections in the retina.
UNC79	Protein unc-79 homolog	Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
SLC39A8	Metal cation symporter ZIP8	Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity.
BLTP3A	Bridge-like lipid transfer protein family member 3A	Tube-forming lipid transport protein which probably mediates the transfer of lipids between membranes at organelle contact sites.
CNGA4	Cyclic nucleotide-gated channel alpha-4	Pore-forming subunit of the olfactory cyclic nucleotide-gated channel.
TAFA5	Chemokine-like protein TAFA-5	Acts as a chemokine-like protein by regulating cell proliferation and migration through activation of G protein-coupled receptors (GPCRs), such as S1PR2 and FPR2.
ADARB1	Double-stranded RNA-specific editase 1	Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing.
HAPLN1	Hyaluronan and proteoglycan link protein 1	Stabilizes the aggregates of proteoglycan monomers with hyaluronic acid in the extracellular cartilage matrix.
COX8C	Cytochrome c oxidase subunit 8C, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
VCAN	Versican core protein	May play a role in intercellular signaling and in connecting cells with the extracellular matrix.
ANO10	Anoctamin-10	Does not exhibit calcium-activated chloride channel (CaCC) activity.
KLHL26	Kelch-like protein 26	May play a role in endo(sarco)plasmic reticulum (ER/SR) mitochondrial signaling.
CRTC3	CREB-regulated transcription coactivator 3	Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites.
PROX2	Prospero homeobox protein 2	Transcription regulator.
DCC	Netrin receptor DCC	Receptor for netrin required for axon guidance.
MON1A	Vacuolar fusion protein MON1 homolog A	Plays an important role in membrane trafficking through the secretory apparatus.
TSKU	Tsukushi	Contributes to various developmental events and other processes such as wound healing and cholesterol homeostasis through its interactions with multiple signaling pathways.
KNDC1	Kinase non-catalytic C-lobe domain-containing protein 1	RAS-Guanine nucleotide exchange factor (GEF) that controls the negative regulation of neuronal dendrite growth by mediating a signaling pathway linking RAS and MAP2.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
DPYD	Dihydropyrimidine dehydrogenase [NADP(+)]	Involved in pyrimidine base degradation.
SNRK	SNF-related serine/threonine-protein kinase	May play a role in hematopoietic cell proliferation or differentiation.

Protein-family classification

Druggable: 27 · Difficult: 9 · Unknown: 39 · Druggable fraction: 0.36

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
Antibody/Immunoglobulin	9	3.5×	0.011
Complement	2	7.2×	0.176
Kinase	5	1.9×	0.491
Transporter	2	2.1×	0.690
Ion channel	1	1.5×	0.905
Protease	2	1.0×	0.905
Other/Unknown	39	0.9×	0.905
Scaffold/PPI	3	0.7×	0.905
Transcription factor	6	0.7×	0.905
Enzyme (other)	4	0.6×	0.905
GPCR	2	0.6×	0.905

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU4-1	Other/Unknown	no
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SLCO3A1	Transporter	yes		Kazal_dom, OATP, Kazal_dom_sf
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
BTN1A1	Antibody/Immunoglobulin	yes		B30.2/SPRY, Ig_sub, SPRY_dom
BTN2A1	Antibody/Immunoglobulin	yes		B30.2/SPRY, Ig_sub, SPRY_dom
BTN3A3	Antibody/Immunoglobulin	yes		B30.2/SPRY, Ig_sub, SPRY_dom
STK24	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
SUOX	Enzyme (other)	yes	1.8.3.1	OxRdtase_Mopterin-bd_dom, Cyt_B5-like_heme/steroid-bd, MoCF_OxRdtse_dimer
TRAF3	Transcription factor	no		Znf_TRAF, Znf_RING, MATH/TRAF_dom
EPCIP	Other/Unknown	no		ECPIP
TMEM59L	Other/Unknown	no		Uncharacterised_TMEM59
PGPEP1	Protease	yes	3.4.19.3	Peptidase_C15, Peptidase_C15-like, PGPEP1_Glu_AS
CA10	Other/Unknown	no		CA_dom, Carbonic_anhydrase_a-class, CA_dom_sf
CNTNAP2	Other/Unknown	no		FA58C, EGF, Laminin_G
FOXP2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
CELF4	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, CELF3/4/5/6_RRM1
CSMD1	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
CCKBR	GPCR	yes		GPCR_Rhodpsn, Gastrin_rcpt, Cholcskin_rcpt
RERG	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
NAV3	Other/Unknown	no		CH_dom, AAA+_ATPase, ATPase_AAA_core
CRTC1	Other/Unknown	no		TORC_N, TORC_M, TORC_C
MAML3	Other/Unknown	no		Mastermind-like_N, MAML1-3, MAML_N_sf
MRM2	Enzyme (other)	yes	2.1.1.166	RNA_MeTrfase_FtsJ_dom, rRNA-MeTfrase_E, SAM-dependent_MTases_sf
SORCS3	Antibody/Immunoglobulin	yes		PKD_dom, VPS10, Ig-like_fold
NEBL	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulette_SH3
ADAMTS17	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
LSM4	Other/Unknown	no		Sm_dom_euk/arc, LSM_dom_sf, LSm4/Sm_D1/D3
NEGR1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
HCG11	Other/Unknown	no
CDK2	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
YLPM1	Other/Unknown	no		YLP_motif_con_p1, P-loop_NTPase, Spectrin_YLPM1-like
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
SDK1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
UNC79	Other/Unknown	no		ARM-type_fold, UNC79
SLC39A8	Transporter	yes		ZIP, ZIP_Transporter
BLTP3A	Other/Unknown	no		BLTP3A/B
CNGA4	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
TAFA5	Other/Unknown	no		Chemokine-like_TAFA, TAFA-5
ADARB1	Enzyme (other)	yes	3.5.4.37	A_deamin, IL1/FGF, dsRBD_dom
HAPLN1	Antibody/Immunoglobulin	yes		Link_dom, Ig_sub, Ig-like_dom
COX8C	Other/Unknown	no		Cyt_c_oxidase_su8, Cyt_c_oxidase_su8_sf
VCAN	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, Link_dom
RBM43	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
ANO10	Other/Unknown	no		Anoctamin, Anoctamin_TM
KLHL26	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
REX1BD	Other/Unknown	no		REX1-B
CRTC3	Other/Unknown	no		TORC_N, TORC_M, TORC_C
PROX2	Transcription factor	no		Homeodomain-like_sf, Homeo_prospero_dom, Homeo_prospero_dom_sf
DCC	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

64 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	6
male germ line stem cell (sensu Vertebrata) in testis	6
cortical plate	6
primordial germ cell in gonad	5
granulocyte	5
monocyte	5
tendon of biceps brachii	5
germinal epithelium of ovary	5
buccal mucosa cell	4
left testis	4
right testis	4
pancreatic ductal cell	4
secondary oocyte	4
mononuclear cell	4
right hemisphere of cerebellum	4
cerebellar cortex	4
adrenal tissue	3
blood	3
colonic epithelium	3
endothelial cell	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU4-1	102	ubiquitous	marker	adrenal tissue, sural nerve, blood
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
SLCO3A1	279	ubiquitous	marker	buccal mucosa cell, endothelial cell, C1 segment of cervical spinal cord
BRAP	286	ubiquitous	marker	left testis, right testis, testis
BTN1A1	33	tissue_specific	marker	primordial germ cell in gonad, pancreatic ductal cell, colonic epithelium
BTN2A1	286	ubiquitous	marker	granulocyte, spleen, cerebellar hemisphere
BTN3A3	282	ubiquitous	marker	granulocyte, spleen, leukocyte
STK24	295	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, amniotic fluid
SUOX	267	ubiquitous	marker	right lobe of liver, right adrenal gland, right adrenal gland cortex
TRAF3	258	ubiquitous	marker	cartilage tissue, monocyte, mononuclear cell
EPCIP	110	tissue_specific	marker	ovary, left ovary, male germ line stem cell (sensu Vertebrata) in testis
TMEM59L	182	ubiquitous	marker	right hemisphere of cerebellum, right frontal lobe, cerebellar hemisphere
PGPEP1	263	ubiquitous	marker	cardia of stomach, renal medulla, tendon of biceps brachii
CA10	167	tissue_specific	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
CNTNAP2	127	broad	marker	corpus callosum, superior frontal gyrus, C1 segment of cervical spinal cord
FOXP2	237	broad	marker	buccal mucosa cell, tibialis anterior, mucosa of paranasal sinus
CELF4	183	broad	marker	cerebellar cortex, cerebellar hemisphere, Brodmann (1909) area 9
CSMD1	179	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex
CCKBR	148	broad	marker	Brodmann (1909) area 10, frontal pole, prefrontal cortex
RERG	247	broad	marker	germinal epithelium of ovary, cauda epididymis, body of uterus
NAV3	232	ubiquitous	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
CRTC1	218	ubiquitous	marker	olfactory bulb, type B pancreatic cell, paraflocculus
MAML3	235	ubiquitous	marker	germinal epithelium of ovary, esophagus squamous epithelium, corpus epididymis
MRM2	140	ubiquitous	yes	primordial germ cell in gonad, gastrocnemius, muscle of leg
SORCS3	118	broad	marker	ventricular zone, cortical plate, Brodmann (1909) area 10
NEBL	282	broad	marker	heart right ventricle, myocardium, cranial nerve II
ADAMTS17	177	broad	marker	thymus, primordial germ cell in gonad, right lobe of liver
LSM4	300	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
NEGR1	242	broad	marker	Brodmann (1909) area 46, Brodmann (1909) area 23, occipital lobe
HCG11	202	ubiquitous	marker	calcaneal tendon, cortical plate, monocyte

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK2	9,236
APOB	5,244
TMEM59L	4,486
ERBB4	4,325
TRAF3	3,493
SUOX	3,449
ATXN2	3,360
HLA-B	3,209
HMGN4	3,148
LSM4	2,958

Intra-cohort edges

A	B	Sources
ATXN2	SH2B3	string_interaction
BTN1A1	NEGR1	intact
CNTNAP2	FOXP1	string_interaction
CNTNAP2	FOXP2	string_interaction
CRTC1	CRTC3	string_interaction
CRTC1	MAML3	string_interaction
DCC	EIF2B2	intact
ELFN1	GRM8	string_interaction
FARP1	LSM4	intact
FOXP1	FOXP2	biogrid_interaction, intact
HAPLN1	VCAN	biogrid_interaction
NEBL	TAFA5	biogrid_interaction, intact
NEGR1	SORCS3	string_interaction
PROX2	YLPM1	string_interaction

Structural data

PDB: 34 · AlphaFold-only: 33 · No structure: 8

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK2	P24941	521
HLA-B	P01889	237
STK24	Q9Y6E0	40
BTN2A1	Q7KYR7	33
EIF2B2	P49770	27
LSM4	Q9Y4Z0	20
ERBB4	Q15303	14
ADARB1	P78563	13
DEPDC5	O75140	11
TRAF3	Q13114	10
BTN3A3	O00478	9
DCC	P43146	9
GRM8	O00222	8
APOB	P04114	8
CCKBR	P32239	5
ANO10	Q9NW15	5
MRM2	Q9UI43	4
CRTC1	Q6UUV9	3
UNC79	Q9P2D8	3
FOXP2	O15409	2
CELF4	Q9BZC1	2
NEGR1	Q7Z3B1	2
CNGA4	Q8IV77	2
MON1A	Q86VX9	2
ATXN2	Q99700	1
SUOX	P51687	1
CNTNAP2	Q9UHC6	1
CSMD1	Q96PZ7	1
RERG	Q96A58	1
NEBL	O76041	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPYD	Q12882	96.23
PGPEP1	Q9NXJ5	93.62
HAPLN1	P10915	89.64
TSKU	Q8WUA8	86.55
CA10	Q9NS85	85.65
BTN1A1	Q13410	84.67
TAFA5	Q7Z5A7	83.74
LYG1	Q8N1E2	82.65
MRLN	P0DMT0	81.26
COX8C	Q7Z4L0	78.94
RBM43	Q6ZSC3	77.12
EPCIP	Q9NYP8	76.98
BRAP	Q7Z569	76.92
SORCS3	Q9UPU3	75.70
SLCO3A1	Q9UIG8	75.19
REX1BD	Q96EN9	74.21
SLC39A8	Q9C0K1	73.46
SDK1	Q7Z5N4	72.92
ADAMTS17	Q8TE56	70.06
BLTP3A	Q6BDS2	67.37
HMGN4	O00479	65.41
SH2B3	Q9UQQ2	63.45
ELFN1	P0C7U0	62.62
TMEM59L	Q9UK28	61.70
KNDC1	Q76NI1	61.25
PROX2	Q3B8N5	60.97
AFF3	P51826	52.20
CRTC3	Q6UUV7	49.61
NAV3	Q8IVL0	48.21
MAML3	Q96JK9	47.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 317. Enrichment computed across 87 evidence-associated genes (47 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 47 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Butyrophilin (BTN) family interactions	3	56.1×	0.006	BTN1A1, BTN2A1, BTN3A3
Heme signaling	4	18.3×	0.010	CRTC1, CRTC3, APOB, NRIP1
Expression of BMAL (ARNTL), CLOCK, and NPAS2	3	18.7×	0.057	CRTC1, CRTC3, NRIP1
SDK interactions	1	121.5×	0.253	SDK1
C6 deamination of adenosine	1	121.5×	0.253	ADARB1
Formation of editosomes by ADAR proteins	1	121.5×	0.253	ADARB1
TRAF3 deficiency - HSE	1	81.0×	0.253	TRAF3
Cam-PDE 1 activation	1	60.7×	0.253	PDE1C
Scavenging by Class H Receptors	1	60.7×	0.253	APOB
Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes	1	60.7×	0.253	CDK2
DSCAM interactions	1	48.6×	0.253	DCC
VLDL assembly	1	48.6×	0.253	APOB
Chylomicron clearance	1	48.6×	0.253	APOB
NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis	1	48.6×	0.253	NRIP1
Sulfide oxidation to sulfate	1	40.5×	0.253	SUOX
Scavenging by Class F Receptors	1	40.5×	0.253	APOB
PTK6 Regulates Cell Cycle	1	40.5×	0.253	CDK2
LDL remodeling	1	40.5×	0.253	APOB
VLDL clearance	1	40.5×	0.253	APOB
G2 Phase	1	34.7×	0.253	CDK2
Defective CHST3 causes SEDCJD	1	30.4×	0.253	VCAN
Defective CHST14 causes EDS, musculocontractural type	1	30.4×	0.253	VCAN
Defective CHSY1 causes TPBS	1	30.4×	0.253	VCAN
Netrin mediated repulsion signals	1	27.0×	0.253	DCC
Recycling of eIF2:GDP	1	27.0×	0.253	EIF2B2
rRNA processing in the mitochondrion	1	27.0×	0.253	MRM2
Downregulation of ERBB4 signaling	1	24.3×	0.253	ERBB4
Caspase activation via Dependence Receptors in the absence of ligand	1	24.3×	0.253	DCC
Zinc transporters	1	24.3×	0.253	SLC39A8
Zinc influx into cells by the SLC39 gene family	1	24.3×	0.253	SLC39A8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 74 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
spinal cord ventral commissure morphogenesis	2	151.8×	0.022	ADARB1, DCC
regulation of interleukin-12 production	2	113.9×	0.022	FOXP1, HLA-B
T cell receptor signaling pathway	5	10.3×	0.022	BTN1A1, BTN2A1, BTN3A3, EIF2B2, PDE4B
negative regulation of receptor signaling pathway via STAT	2	91.1×	0.023	SH2B3, PTPRT
regulation of cytokine production	4	13.4×	0.023	BTN1A1, BTN2A1, BTN3A3, TRAF3
synapse assembly	4	12.5×	0.025	SDK1, ELFN1, ERBB4, FARP1
negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway	2	65.1×	0.029	CRTC3, PDE4B
vocal learning	2	56.9×	0.034	CNTNAP2, FOXP2
neutrophil homeostasis	2	41.4×	0.058	SH2B3, PDE4B
thalamus development	2	38.0×	0.063	CNTNAP2, OLIG2
ovarian follicle rupture	1	227.7×	0.075	NRIP1
purine nucleobase catabolic process	1	227.7×	0.075	DPYD
thymidine catabolic process	1	227.7×	0.075	DPYD
beta-alanine biosynthetic process	1	227.7×	0.075	DPYD
hypoglossal nerve morphogenesis	1	227.7×	0.075	ADARB1
caudate nucleus development	1	227.7×	0.075	FOXP2
putamen development	1	227.7×	0.075	FOXP2
TMP catabolic process	1	227.7×	0.075	DPYD
leukocyte adhesion to arterial endothelial cell	1	227.7×	0.075	SLC39A8
plasma membrane selenite transport	1	227.7×	0.075	SLC39A8
regulation of macrophage colony-stimulating factor production	1	227.7×	0.075	FOXP1
regulation of retina development in camera-type eye	1	227.7×	0.075	CELF4
mitochondrial manganese ion transmembrane transport	1	227.7×	0.075	SLC39A8
striatum development	2	30.4×	0.075	CNTNAP2, FOXP1
P-body assembly	2	28.5×	0.075	ATXN2, LSM4
vocalization behavior	2	24.0×	0.075	CNTNAP2, FOXP2
energy homeostasis	3	11.0×	0.075	CRTC1, CRTC3, TSKU
central nervous system development	4	6.2×	0.075	HAPLN1, VCAN, PROX2, EIF2B2
negative regulation of cell migration	4	6.0×	0.075	STK24, NAV3, ADARB1, PTPRT
cell adhesion	7	3.5×	0.075	CNTNAP2, HAPLN1, VCAN, RND3, NCAM1, PCDH9, PTPRT

Therapeutics

Drugs indicated for this disease

16 approved, 18 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bismuth Subcitrate Potassium	Approved (phase 4)
Carbenoxolone	Approved (phase 4)
Cimetidine	Approved (phase 4)
Dexlansoprazole	Approved (phase 4)
Famotidine	Approved (phase 4)
Lansoprazole	Approved (phase 4)
Misoprostol	Approved (phase 4)
Nizatidine	Approved (phase 4)
Omeprazole	Approved (phase 4)
Pirenzepine	Approved (phase 4)
Proglumide	Approved (phase 4)
Rabeprazole	Approved (phase 4)
Ranitidine	Approved (phase 4)
Sodium Bicarbonate	Approved (phase 4)
Sucralfate	Approved (phase 4)
Vonoprazan	Approved (phase 4)
Abeprazan	Phase 3 (in late-stage trials)
Alginic Acid	Phase 3 (in late-stage trials)
Baclofen	Phase 3 (in late-stage trials)
Desipramine	Phase 3 (in late-stage trials)
Domperidone	Phase 3 (in late-stage trials)
Esomeprazole	Phase 3 (in late-stage trials)
Gefarnate	Phase 3 (in late-stage trials)
Ilaprazole	Phase 3 (in late-stage trials)
Imipramine	Phase 3 (in late-stage trials)
Lafutidine	Phase 3 (in late-stage trials)
Melatonin	Phase 3 (in late-stage trials)
Nortriptyline	Phase 3 (in late-stage trials)
Pantoprazole	Phase 3 (in late-stage trials)
Rebamipide	Phase 3 (in late-stage trials)
Sodium Alginate	Phase 3 (in late-stage trials)
Tegaserod	Phase 3 (in late-stage trials)
Tegoprazan	Phase 3 (in late-stage trials)
Teprenone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Arbaclofen Placarbil, Charcoal, Activated, Fexofenadine, Fluoxetine, Lactose, Anhydrous.

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 68

Druggability breadth: 22 of 87 evidence-associated genes (25%) 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
STK24	NERATINIB
CCKBR	SINCALIDE
CDK2	PALBOCICLIB
SNRK	FEDRATINIB
ERBB4	MOBOCERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK2	85	4
ERBB4	47	4
CCKBR	33	4
STK24	18	4
SNRK	3	4
GRM8	3	3
DPYD	1	3
RNU4-1	0	0
ATXN2	0	0
SLCO3A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NERATINIB	4	ERBB4, STK24
BOSUTINIB	4	ERBB4, STK24
GILTERITINIB	4	CDK2, STK24
NINTEDANIB	4	CDK2, STK24
SUNITINIB	4	SNRK, STK24
QUIZARTINIB	4	CDK2, STK24
SINCALIDE	4	CCKBR
CHLORDIAZEPOXIDE	4	CCKBR
CANDESARTAN CILEXETIL	4	CCKBR
CLOTRIMAZOLE	4	CCKBR
RIMONABANT	4	CCKBR
INDOCYANINE GREEN ACID FORM	4	CCKBR
FIDAXOMICIN	4	CCKBR
PENTAGASTRIN	4	CCKBR
FLUNITRAZEPAM	4	CCKBR
NITAZOXANIDE	4	CCKBR
ILOPERIDONE	4	CCKBR
DESOGESTREL	4	CCKBR
AZLOCILLIN	4	CCKBR
RIFAXIMIN	4	CCKBR
ISRADIPINE	4	CCKBR
FLUTRIMAZOLE	4	CCKBR
EFAVIRENZ	4	CCKBR
ENCORAFENIB	4	CCKBR
FLUOXETINE	4	CCKBR
LANSOPRAZOLE	4	CCKBR
APOMORPHINE	4	CCKBR
TAMOXIFEN	4	CCKBR
DOCETAXEL ANHYDROUS	4	CCKBR
LEFLUNOMIDE	4	CCKBR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
CDK2	2,469	Binding:2394, Functional:59, ADMET:14, Toxicity:2
ERBB4	591	Binding:579, ADMET:8, Functional:4
CCKBR	374	Binding:322, Functional:51, Toxicity:1
STK24	314	Binding:314
SNRK	111	Binding:111
GRM8	111	Functional:57, Binding:54
SLCO3A1	9	Functional:9
ATXN2	5	Binding:3, Functional:2
ADARB1	5	Binding:5
DPYD	3	Functional:2, Binding:1
BRAP	2	Binding:2
PGPEP1	2	Binding:2
BTN2A1	1	Binding:1
KLHL26	1	Binding:1
EIF2B2	1	Binding:1
HIVEP2	1	Binding:1
HLA-B	1	Binding:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SUOX	1.8.3.1	sulfite oxidase
PGPEP1	3.4.19.3	pyroglutamyl-peptidase I
MRM2	2.1.1.166, 2.1.1.B123	23S rRNA (uridine2552-2’-O)-methyltransferase,
CDK2	2.7.11.22	cyclin-dependent kinase
ADARB1	3.5.4.37	double-stranded RNA adenine deaminase
DPYD	1.3.1.2	dihydropyrimidine dehydrogenase (NADP+)
ERBB4	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
STK24	314
CCKBR	374
CDK2	2,469
SNRK	111
ERBB4	591
GRM8	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 70; with CPIC/DPWG dosing guidelines: 2.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
DPYD	1
HLA-B	1

Chemical tractability of cohort targets

29 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)
NERATINIB	4	ERBB4, STK24
BOSUTINIB	4	ERBB4, STK24
GILTERITINIB	4	CDK2, STK24
NINTEDANIB	4	CDK2, STK24
SUNITINIB	4	SNRK, STK24
QUIZARTINIB	4	CDK2, STK24
SINCALIDE	4	CCKBR
CHLORDIAZEPOXIDE	4	CCKBR
CANDESARTAN CILEXETIL	4	CCKBR
CLOTRIMAZOLE	4	CCKBR
RIMONABANT	4	CCKBR
INDOCYANINE GREEN ACID FORM	4	CCKBR
FIDAXOMICIN	4	CCKBR
PENTAGASTRIN	4	CCKBR
FLUNITRAZEPAM	4	CCKBR
NITAZOXANIDE	4	CCKBR
ILOPERIDONE	4	CCKBR
DESOGESTREL	4	CCKBR
AZLOCILLIN	4	CCKBR
RIFAXIMIN	4	CCKBR
ISRADIPINE	4	CCKBR
FLUTRIMAZOLE	4	CCKBR
EFAVIRENZ	4	CCKBR
ENCORAFENIB	4	CCKBR
FLUOXETINE	4	CCKBR
APOMORPHINE	4	CCKBR
TAMOXIFEN	4	CCKBR
DOCETAXEL ANHYDROUS	4	CCKBR
LEFLUNOMIDE	4	CCKBR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	STK24, CCKBR, CDK2, SNRK, ERBB4
B	Phased (≥1) drug, not yet approved	2	DPYD, GRM8
C	Druggable family + PDB, no drug	10	BTN2A1, BTN3A3, SUOX, CSMD1, MRM2, NEGR1, CNGA4, ADARB1, DCC, HLA-B
D	Druggable family + AlphaFold only, no drug	10	SLCO3A1, BTN1A1, PGPEP1, SORCS3, ADAMTS17, SDK1, SLC39A8, HAPLN1, VCAN, KNDC1
E	Difficult family or no structure, no drug	48	RNU4-1, ATXN2, BRAP, TRAF3, EPCIP, TMEM59L, CA10, CNTNAP2, FOXP2, CELF4 (+38 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNU4-1	0	—
ATXN2	5	—
SLCO3A1	9	—
BRAP	2	—
BTN1A1	0	—
BTN2A1	1	—
BTN3A3	0	—
SUOX	0	—
TRAF3	0	—
EPCIP	0	—
TMEM59L	0	—
PGPEP1	2	—
CA10	0	—
CNTNAP2	0	—
FOXP2	0	—
CELF4	0	—
CSMD1	0	—
RERG	0	—
NAV3	0	—
CRTC1	0	—
MAML3	0	—
MRM2	0	—
SORCS3	0	—
NEBL	0	—
ADAMTS17	0	—
LSM4	0	—
NEGR1	0	—
HCG11	0	—
YLPM1	0	—
DEPDC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 777.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	485
PHASE4	87
PHASE3	86
PHASE1	61
PHASE2	41
PHASE2/PHASE3	9
PHASE1/PHASE2	6
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06241183	PHASE4	RECRUITING	Famotidine and Antacids for Treatment of Dyspepsia
NCT06255886	PHASE4	RECRUITING	Treatment of Gastroesophageal Reflux Disease in Infants
NCT06564246	PHASE4	RECRUITING	Clinical Study Evaluating The Role of Vonoprazan Versus Pantoprazole in Patients With Gastroesophageal Reflux Disease
NCT06991348	PHASE4	RECRUITING	Clinical Trial for the Comparative Evaluation of Acid Suppression and Symptom Management of Gastroesophageal Reflux Disease With the Administration of Tegoprazan or Pantoprazole
NCT07268820	PHASE4	RECRUITING	Heartburn, Gastroesophageal Reflux Disease
NCT00184522	PHASE4	COMPLETED	On Demand Treatment of Reflux Disease
NCT00206180	PHASE4	COMPLETED	NEXIUM® in the Treatment of Moderate and Severe Erosive Esophagitis
NCT00216489	PHASE4	COMPLETED	A Study of the Safety of Rabeprazole Administered to Adults With Gastroesophageal Reflux Disease (GERD)
NCT00228527	PHASE4	COMPLETED	Esomeprazole for Treatment of GERD in Pediatric Patients
NCT00237367	PHASE4	COMPLETED	A Study of Rabeprazole and Pantoprazole on Stomach Acid and Esophageal Acid Exposure in Patients With Gastroesophageal Reflux Disease (GERD) and a History of Nighttime Heartburn
NCT00242736	PHASE4	COMPLETED	An Open-Label Study of Once-Daily Oral Administration of Esomeprazole 40 mg in Patients With Symptoms of Gastroesophageal Reflux Disease (GERD)
NCT00246909	PHASE4	COMPLETED	Determination of the Minimal Clinically Important Difference After Treatment With Pantoprazole in Patients With Symptoms of Acid Reflux (Gastroesophageal Reflux Disease) (BY1023/M3-340)
NCT00251732	PHASE4	COMPLETED	Role of Pain Modulation in GERD Patients Who Failed Standard Dose Proton Pump Inhibitors (PPI)
NCT00261339	PHASE4	COMPLETED	Determination of a Questionnaire After Treatment With Pantoprazole at Full Dose and Half Dose in Adult Patients With Symptoms of Acid Reflux (Gastroesophageal Reflux Disease) (BY1023/UK-506)
NCT00272701	PHASE4	COMPLETED	Esomeprazole in PPI Failures - IMPROVE
NCT00287339	PHASE4	COMPLETED	The Utility of Nexium in Chronic Cough and Reflux Disease
NCT00287391	PHASE4	COMPLETED	Sleep Disorders and Gastroesophageal Reflux Disease (GERD)
NCT00291746	PHASE4	COMPLETED	Validation of RDQ Questionnaire
NCT00295685	PHASE4	COMPLETED	Nexium 40mg Once Daily vs Prevacid 30mg Twice a Day for Control of Severe GERD
NCT00299845	PHASE4	WITHDRAWN	Randomized Trial for Pharmacogenomics-based Proton Pump Inhibitor Therapy in Children
NCT00304421	PHASE4	COMPLETED	Comparison of the Nighttime Effects of Two Different Drugs on Subjects With GERD
NCT00318084	PHASE4	COMPLETED	PPI Test in GP Patients
NCT00318968	PHASE4	COMPLETED	Nexium RESPONSE Trial
NCT00325676	PHASE4	COMPLETED	Comparison of the Classical Healing Concept With the Complete Remission Concept After Treatment With Pantoprazole in Adult Patients With Erosive GERD (Gastroesophageal Reflux Disease) (BY1023/M3-342)
NCT00343161	PHASE4	COMPLETED	Symptom Adapted Therapy in GERD Patients
NCT00354757	PHASE4	COMPLETED	CYP2C19 Genetic Polymorphism on the Accuracy of Proton-Pump Inhibitor Testing
NCT00373997	PHASE4	COMPLETED	Esophageal and Laryngeal Tissue Changes in Patients Suspected of Having Laryngopharyngeal Reflux
NCT00392002	PHASE4	COMPLETED	Examine National Characteristics & Outcome Measures of GERD Patients Using the PPI Acid Suppression Symptom (PASS) Test for Response
NCT00410592	PHASE4	COMPLETED	Evaluation of 24-Hour Intragastric pH Using Esomeprazole, Lansoprazole, and Pantoprazole in Hispanic Patients With GERD
NCT00444145	PHASE4	COMPLETED	Do Laryngeal Tissue Changes in Patients Suspected of Having Laryngopharyngeal Reflux Predict Response to Treatment?
NCT00444275	PHASE4	COMPLETED	Nexium (Esomeprazole) in Symptom Adapted Therapy in GERD Patients
NCT00449813	PHASE4	TERMINATED	The CONQUEST-Study. Evaluation of Clinical Endpoints for Treatment-induced Changes in GERD-related Symptoms (BY1023/NL511)
NCT00472550	PHASE4	COMPLETED	Esomeprazole and Gastric Emptying of Beer
NCT00476398	PHASE4	COMPLETED	Evaluation of Patients With Non-cardiac Chest Pain
NCT00492622	PHASE4	COMPLETED	Pharmacokinetics of Immediate-Release vs. Delayed-Release Omeprazole in Gastroparesis
NCT00537732	PHASE4	TERMINATED	Omeprazole and Reflux Disease - Improvement of Clinical Outcome by Genotype-adjusted Dosing
NCT00574925	PHASE4	COMPLETED	Study to Assess Management Strategies for the Use of Esomeprazole (Nexium) in Helicobacter Pylori Infected Patients
NCT00582972	PHASE4	COMPLETED	Does Omeprazole Decrease Intestinal Calcium Absorption?
NCT00625495	PHASE4	COMPLETED	Study Comparing the Effects of Esomeprazole Adminstered Orally and Intravenously on Basal and Pentrigastrin-stimulated Acid Output in Subjects With Symptoms of Gastroesophageal Reflux Disease (GERD)
NCT00626262	PHASE4	COMPLETED	Open, Randomized, Two Way Crossover Study Comparing the Effect of Esomeprazole Adminstered Orally and iv

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ESOMEPRAZOLE	4	93
RABEPRAZOLE	4	51
PANTOPRAZOLE	4	26
DEXLANSOPRAZOLE	4	15
LANSOPRAZOLE	4	12
DOMPERIDONE	4	11
OMEPRAZOLE	4	11
VONOPRAZAN	4	8
RANITIDINE	4	6
TEGASEROD	4	6
COLESEVELAM HYDROCHLORIDE	4	4
FAMOTIDINE	4	4
BACLOFEN	4	3
CISAPRIDE	4	3
CITALOPRAM	4	3
SUCRALFATE	4	3
IMIPRAMINE	4	2
LIDOCAINE HYDROCHLORIDE	4	2
NIZATIDINE	4	2
PRUCALOPRIDE	4	2
AMILORIDE	4	1
AMITRIPTYLINE	4	1
AMITRIPTYLINE HYDROCHLORIDE	4	1
ATOVAQUONE	4	1
BUSPIRONE	4	1
CALCIUM	4	1
CIMETIDINE	4	1
CROMOLYN SODIUM	4	1
DESIPRAMINE	4	1
ERYTHROMYCIN	4	1

Cohort genes: RNU4-1, ATXN2, SLCO3A1, BRAP, BTN1A1, BTN2A1, BTN3A3, STK24, SUOX, TRAF3, EPCIP, TMEM59L, PGPEP1, CA10, CNTNAP2, FOXP2, CELF4, CSMD1, CCKBR, RERG, NAV3, CRTC1, MAML3, MRM2, SORCS3, NEBL, ADAMTS17, LSM4, NEGR1, HCG11, CDK2, YLPM1, DEPDC5, SDK1, UNC79, SLC39A8, BLTP3A, CNGA4, TAFA5, ADARB1, HAPLN1, COX8C, VCAN, RBM43, ANO10, KLHL26, REX1BD, CRTC3, PROX2, DCC, LYG1, MON1A, TSKU, KNDC1, SH2B3, DPYD, SNRK, EIF2B2, SNORD114-31, ELFN1, ERBB4, FARP1, FOXP1, GRM8, MRLN, HIVEP2, HLA-B, HMGN4, LINC01422, PPP3CA-DT, APOB, AFF3
Drugs: Esomeprazole, Rabeprazole, Pantoprazole, Dexlansoprazole, Lansoprazole, Domperidone, Omeprazole, Vonoprazan, Ranitidine, Tegaserod, Colesevelam, Famotidine, Baclofen, Cisapride, Citalopram, Sucralfate, Imipramine, Lidocaine, Nizatidine, Prucalopride, Amiloride, Amitriptyline, Atovaquone, Buspirone, Calcium, Cimetidine, Cromolyn, Desipramine, Erythromycin