Dental caries

Summary

Dental caries (MONDO:0005276) is a disease (an umbrella term covering 5 Mondo subtypes) with 75 cohort genes (334 GWAS associations across 42 studies) and 655 clinical trials. The dominant Reactome pathway is Alpha-defensins (4 cohort genes). Top therapeutic interventions include chlorhexidine, sodium fluoride, and ketamine.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 334
• ClinVar variants: 4
• Clinical trials: 655

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dental caries
Mondo ID	MONDO:0005276
EFO	EFO:0003819
MeSH	D003731
DOID	DOID:216
ICD-10-CM	K02
ICD-11	1983306720
SNOMED CT	80967001
UMLS	C0011334
MedGen	8288
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 334 GWAS associations (42 studies).

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › tooth disorder › tooth hard tissue disease › dental caries

Related subtypes (6): tooth resorption, dental enamel hypoplasia, dentin sensitivity, hypercementosis, tooth ankylosis, dentin dysplasia

Subtypes (5): dentin caries, odontoclasia, enamel caries, pit and fissure surface dental caries, smooth surface dental caries

Genetics & variants

GWAS landscape

334 GWAS associations across 42 studies. Top hits map to 27 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1122171	3e-62	PITX1-AS1	T	0.04
rs9366651	3e-28	H3C9P - BTN3A2	T	0.03
rs72748935	1e-26	CA12	T	0.03
rs9257805	2e-25	OR5V1	G	10.42
rs9358919	4e-24	H4C8 - H3C9P	C	10.13
rs121908120	2e-22	WNT10A	A	0.08
rs1062070	7e-22	RNF5	G	9.61
rs7752448	1e-21	ZSCAN31	G	9.55
rs1853098	2e-21	OR2W4P - ZSCAN16-AS1	G	9.51
rs200949	4e-21	H1-5 - H3C11	G	9.43
rs3129817	1e-20	UBQLN1P1 - MICC	A	9.33
rs9379832	2e-20	H2BC6 - H4C4	A	9.25
rs1264347	5e-20	LINC00243 - LINC02570	T	9.16
rs9273325	7e-20	HLA-DQA1 - HLA-DQB1	A	9.13
rs3094671	3e-19	HCG22 - RNU6-1133P	C	8.98
rs1611583	4e-19	POLR1HASP, POLR1HASP	G	8.94
rs7748167	6e-19	H2BP5 - SLC17A2	C	8.89
rs67682613	7e-19	NEU1	A	8.87
rs3130247	8e-19	GNL1	C	8.86
rs9268137	2e-18	TSBP1-AS1	A	8.76
rs402175	4e-18	LINC02571 - HLA-B	A	8.67
rs34388845	7e-18	SCAND3	G	8.62
rs3095233	1e-17	MICB	G	8.53
rs9468317	1e-17	ZSCAN9	C	8.53
rs1541269	3e-17	TRIM31-AS1 - TRIM40	A	8.46
rs115549271	4e-17	HLA-DRB9 - HLA-DRB5	A	8.41
rs1610638	8e-17	HLA-F-AS1	T	8.33
rs3131783	1e-16	NAPGP2 - MUC21	A	8.3
rs61289879	1e-16	COX11P1 - OR2E1P	A	8.3
rs1064627	2e-16	FLOT1	G	8.24

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90478236	Verma A	2024	79,403	345,413	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST008295	Shungin D	2019	77,714	383,317	Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.
GCST90478235	Verma A	2024	37,171	73,002	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480844	Verma A	2024	37,171	73,002	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90565216	Nogawa S	2024	30,859	14,666	Genome-wide association meta-analysis identifies two novel loci associated with dental caries.
GCST90565218	Nogawa S	2024	30,859	14,666	Genome-wide association meta-analysis identifies two novel loci associated with dental caries.
GCST90478233	Verma A	2024	14,616	40,764	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478239	Verma A	2024	8,626	430,087	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST006312	Haworth S	2018	6,922	10,115	Consortium genome-wide meta-analysis for childhood dental caries traits.
GCST006311	Haworth S	2018	5,875	7,478	Consortium genome-wide meta-analysis for childhood dental caries traits.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	30
intergenic_variant	12
missense_variant	2
synonymous_variant	2
regulatory_region_variant	2
3_prime_UTR_variant	1
splice_polypyrimidine_tract_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1122171	5	135174297	C>T	0.41	intron_variant	PITX1-AS1	3e-62	Tier 4: intronic/intergenic
rs9366651	6	26336468	G>A,T	0.49	intron_variant	H3C9P - BTN3A2	3e-28	Tier 4: intronic/intergenic
rs72748935	15	63347217	T>C	0.46	intron_variant	CA12	1e-26	Tier 4: intronic/intergenic
rs9257805	6	29378552	A>G	0.05	intron_variant	OR5V1	2e-25	Tier 4: intronic/intergenic
rs9358919	6	26287634	C>A,G,T	0.05	intron_variant	H4C8 - H3C9P	4e-24	Tier 4: intronic/intergenic
rs121908120	2	218890289	T>A	0.03	missense_variant	WNT10A	2e-22	Tier 1: coding
rs1062070	6	32180254	A>G	0.05	synonymous_variant	RNF5	7e-22	Tier 4: intronic/intergenic
rs7752448	6	28333322	A>G	0.05	intron_variant	ZSCAN31	1e-21	Tier 4: intronic/intergenic
rs1853098	6	27988277	G>A	0.05	intergenic_variant	OR2W4P - ZSCAN16-AS1	2e-21	Tier 4: intronic/intergenic
rs200949	6	27867657	A>C,G,T	0.05	regulatory_region_variant	H1-5 - H3C11	4e-21	Tier 3: regulatory
rs3129817	6	30374976	G>A	0.05	intergenic_variant	UBQLN1P1 - MICC	1e-20	Tier 4: intronic/intergenic
rs9379832	6	26185972	A>C,G,T	0.05	intron_variant	H2BC6 - H4C4	2e-20	Tier 4: intronic/intergenic
rs1264347	6	30830920	C>T	0.05	intergenic_variant	LINC00243 - LINC02570	5e-20	Tier 4: intronic/intergenic
rs9273325	6	32655416	G>A	0.05	intergenic_variant	HLA-DQA1 - HLA-DQB1	7e-20	Tier 4: intronic/intergenic
rs3094671	6	31076686	T>C	0.05	intergenic_variant	HCG22 - RNU6-1133P	3e-19	Tier 4: intronic/intergenic
rs1611583	6	29883186	A>G,T	0.05	intron_variant	POLR1HASP, POLR1HASP	4e-19	Tier 4: intronic/intergenic
rs7748167	6	25904424	A>C	0.05	intergenic_variant	H2BP5 - SLC17A2	6e-19	Tier 4: intronic/intergenic
rs67682613	6	31858928			3_prime_UTR_variant	NEU1	7e-19	Tier 2: splice/UTR
rs3130247	6	30547266	T>C	0.05	synonymous_variant	GNL1	8e-19	Tier 4: intronic/intergenic
rs9268137	6	32287492	G>A	0.05	intron_variant	TSBP1-AS1	2e-18	Tier 4: intronic/intergenic
rs402175	6	31340940	G>A	0.05	intron_variant	LINC02571 - HLA-B	4e-18	Tier 4: intronic/intergenic
rs34388845	6	28610509	A>G	0.05	intergenic_variant	SCAND3	7e-18	Tier 4: intronic/intergenic
rs3095233	6	31501997	A>G,T	0.05	intron_variant	MICB	1e-17	Tier 4: intronic/intergenic
rs9468317	6	28230678	T>A,C	0.05	intron_variant	ZSCAN9	1e-17	Tier 4: intronic/intergenic
rs1541269	6	30135583	G>A,C,T	0.05	intergenic_variant	TRIM31-AS1 - TRIM40	3e-17	Tier 4: intronic/intergenic
rs115549271	6	32484666	G>A,T	0.05	intron_variant	HLA-DRB9 - HLA-DRB5	4e-17	Tier 4: intronic/intergenic
rs1610638	6	29772700	C>A,G,T	0.05	intron_variant	HLA-F-AS1	8e-17	Tier 4: intronic/intergenic
rs3131783	6	30964291	G>A,C,T	0.05	regulatory_region_variant	NAPGP2 - MUC21	1e-16	Tier 3: regulatory
rs61289879	6	28451385	G>A,T	0.05	intron_variant	COX11P1 - OR2E1P	1e-16	Tier 4: intronic/intergenic
rs1064627	6	30730764	A>C,G,T	0.05	intron_variant	FLOT1	2e-16	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
267815	46;X;t(X;5)(p11.23;q35)dn		Pathogenic	criteria provided, single submitter
56645	NM_152564.5(VPS13B):c.1219C>T (p.Gln407Ter)	VPS13B	Pathogenic	criteria provided, multiple submitters, no conflicts
242886	NM_001001344.3(ATP2B3):c.3594G>T (p.Lys1198Asn)	ATP2B3	Likely pathogenic	criteria provided, single submitter
267831	46;Y;inv(X)(q27q28)		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 43 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SALL1	Orphanet:857	Townes-Brocks syndrome
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral
NHERF1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
KLF11	Orphanet:552	MODY
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
TSPEAR	Orphanet:685067	Hypodontia-scalp hypotrichosis-facial dysmorphism syndrome
TRAF3IP2	Orphanet:1334	Chronic mucocutaneous candidiasis
CA12	Orphanet:542657	Isolated hyperchlorhidrosis
WNT10A	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia
WNT10A	Orphanet:2721	Odonto-onycho-dermal dysplasia
WNT10A	Orphanet:50944	Schöpf-Schulz-Passarge syndrome
WNT10A	Orphanet:99798	Oligodontia
IRX2	Orphanet:457246	Clear cell sarcoma of kidney
ACP4	Orphanet:100031	Hypoplastic amelogenesis imperfecta
SNX10	Orphanet:667	Autosomal recessive malignant osteopetrosis
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
CHST8	Orphanet:263548	Peeling skin syndrome type A
FKBP14	Orphanet:300179	Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency
CLDN10	Orphanet:528105	Hypohidrosis-electrolyte imbalance-lacrimal gland dysfunction-ichthyosis-xerostomia syndrome
IFT88	Orphanet:791	Retinitis pigmentosa
ACAD9	Orphanet:99901	Acyl-CoA dehydrogenase 9 deficiency
VPS13B	Orphanet:193	Cohen syndrome
ADAMTS3	Orphanet:2136	Hennekam syndrome

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	74
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS6KA2	HGNC:10431	ENSG00000071242	Q15349	Ribosomal protein S6 kinase alpha-2	gwas
SALL1	HGNC:10524	ENSG00000103449	Q9NSC2	Sal-like protein 1	gwas
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gwas
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	gwas
SIGLEC9	HGNC:10878	ENSG00000129450	Q9Y336	Sialic acid-binding Ig-like lectin 9	gwas
SLC25A10	HGNC:10980	ENSG00000183048	Q9UBX3	Mitochondrial dicarboxylate carrier	gwas
NHERF1	HGNC:11075	ENSG00000109062	O14745	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	gwas
TAF1B	HGNC:11533	ENSG00000115750	Q53T94	TATA box-binding protein-associated factor RNA polymerase I subunit B	gwas
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	gwas
MPPED2	HGNC:1180	ENSG00000066382	Q15777	Metallophosphoesterase MPPED2	gwas
KLF11	HGNC:11811	ENSG00000172059	O14901	Krueppel-like factor 11	gwas
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gwas
TRPM2	HGNC:12339	ENSG00000142185	O94759	Transient receptor potential cation channel subfamily M member 2	gwas
TWSG1	HGNC:12429	ENSG00000128791	Q9GZX9	Twisted gastrulation protein homolog 1	gwas
TSPEAR	HGNC:1268	ENSG00000175894	Q8WU66	Thrombospondin-type laminin G domain and EAR repeat-containing protein	gwas
ZRANB2	HGNC:13058	ENSG00000132485	O95218	Zinc finger Ran-binding domain-containing protein 2	gwas
SIRAL2	HGNC:1313	ENSG00000100376	Q9NWS6	Protein FAM118A	gwas
ZNF98	HGNC:13174	ENSG00000197360	A6NK75	Zinc finger protein 98	gwas
LGR4	HGNC:13299	ENSG00000205213	Q9BXB1	Leucine-rich repeat-containing G-protein coupled receptor 4	gwas
MEPE	HGNC:13361	ENSG00000152595	Q9NQ76	Matrix extracellular phosphoglycoprotein	gwas
PHTF2	HGNC:13411	ENSG00000006576	Q8N3S3	Protein PHTF2	gwas
RBMS3	HGNC:13427	ENSG00000144642	Q6XE24	RNA-binding motif, single-stranded-interacting protein 3	gwas
TRAF3IP2	HGNC:1343	ENSG00000056972	O43734	E3 ubiquitin ligase TRAF3IP2	gwas
MAML1	HGNC:13632	ENSG00000161021	Q92585	Mastermind-like protein 1	gwas
CA12	HGNC:1371	ENSG00000074410	O43570	Carbonic anhydrase 12	gwas
DMRTA1	HGNC:13826	ENSG00000176399	Q5VZB9	Doublesex- and mab-3-related transcription factor A1	gwas
WNT10A	HGNC:13829	ENSG00000135925	Q9GZT5	Protein Wnt-10a	gwas
LZTS1	HGNC:13861	ENSG00000061337	Q9Y250	Leucine zipper putative tumor suppressor 1	gwas
PMEPA1	HGNC:14107	ENSG00000124225	Q969W9	Protein TMEPAI	gwas
LPAR3	HGNC:14298	ENSG00000171517	Q9UBY5	Lysophosphatidic acid receptor 3	gwas
IRX2	HGNC:14359	ENSG00000170561	Q9BZI1	Iroquois-class homeodomain protein IRX-2	gwas
ACP4	HGNC:14376	ENSG00000142513	Q9BZG2	Testicular acid phosphatase	gwas
SNX7	HGNC:14971	ENSG00000162627	Q9UNH6	Sorting nexin-7	gwas
SNX10	HGNC:14974	ENSG00000086300	Q9Y5X0	Sorting nexin-10	gwas
ARHGEF16	HGNC:15515	ENSG00000130762	Q5VV41	Rho guanine nucleotide exchange factor 16	gwas
CGRRF1	HGNC:15528	ENSG00000100532	Q99675	Cell growth regulator with RING finger domain protein 1	gwas
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	gwas
CHST8	HGNC:15993	ENSG00000124302	Q9H2A9	Carbohydrate sulfotransferase 8	gwas
CD1A	HGNC:1634	ENSG00000158477	P06126	T-cell surface glycoprotein CD1a	gwas
CD1C	HGNC:1636	ENSG00000158481	P29017	T-cell surface glycoprotein CD1c	gwas
CD1D	HGNC:1637	ENSG00000158473	P15813	Antigen-presenting glycoprotein CD1d	gwas
NOD1	HGNC:16390	ENSG00000106100	Q9Y239	Nucleotide-binding oligomerization domain-containing protein 1	gwas
MAP3K7CL	HGNC:16457	ENSG00000156265	P57077	MAP3K7 C-terminal-like protein	gwas
CD33	HGNC:1659	ENSG00000105383	P20138	Myeloid cell surface antigen CD33	gwas
BOC	HGNC:17173	ENSG00000144857	Q9BWV1	Brother of CDO	gwas
ALLC	HGNC:17377	ENSG00000151360	Q8N6M5	Probable inactive allantoicase	gwas
CDH13	HGNC:1753	ENSG00000140945	P55290	Cadherin-13	gwas
CDH9	HGNC:1768	ENSG00000113100	Q9ULB4	Cadherin-9	gwas
LIN7A	HGNC:17787	ENSG00000111052	O14910	Protein lin-7 homolog A	gwas
RHOU	HGNC:17794	ENSG00000116574	Q7L0Q8	Rho-related GTP-binding protein RhoU	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPS6KA2	Ribosomal protein S6 kinase alpha-2	Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of transcription factors, regulates translation, and mediates cellular proliferation, su…
SALL1	Sal-like protein 1	Transcriptional repressor involved in organogenesis.
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.
SIGLEC9	Sialic acid-binding Ig-like lectin 9	Putative adhesion molecule that mediates sialic-acid dependent binding to cells.
SLC25A10	Mitochondrial dicarboxylate carrier	Catalyzes the electroneutral exchange or flux of physiologically important metabolites such as dicarboxylates (malonate, malate, succinate), inorganic sulfur-containing anions, and phosphate, across the mitochondrial inner membrane.
NHERF1	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression.
TAF1B	TATA box-binding protein-associated factor RNA polymerase I subunit B	Component of RNA polymerase I core factor complex that acts as a GTF2B/TFIIB-like factor and plays a key role in multiple steps during transcription initiation such as pre-initiation complex (PIC) assembly and postpolymerase recruitment ev…
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
MPPED2	Metallophosphoesterase MPPED2	Displays low metallophosphoesterase activity (in vitro).
KLF11	Krueppel-like factor 11	Transcription factor.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TRPM2	Transient receptor potential cation channel subfamily M member 2	Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels.
TWSG1	Twisted gastrulation protein homolog 1	May be involved in dorsoventral axis formation.
TSPEAR	Thrombospondin-type laminin G domain and EAR repeat-containing protein	Plays a critical role in tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.
ZRANB2	Zinc finger Ran-binding domain-containing protein 2	Splice factor required for alternative splicing of TRA2B/SFRS10 transcripts.
ZNF98	Zinc finger protein 98	May be involved in transcriptional regulation.
LGR4	Leucine-rich repeat-containing G-protein coupled receptor 4	Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs.
MEPE	Matrix extracellular phosphoglycoprotein	Promotes renal phosphate excretion and inhibits intestinal phosphate absorption.
RBMS3	RNA-binding motif, single-stranded-interacting protein 3	Binds poly(A) and poly(U) oligoribonucleotides.
TRAF3IP2	E3 ubiquitin ligase TRAF3IP2	E3 ubiquitin ligase that catalyzes ‘Lys-63’-linked polyubiquitination of target protein, enhancing protein-protein interaction and cell signaling.
MAML1	Mastermind-like protein 1	Acts as a transcriptional coactivator for NOTCH proteins.
CA12	Carbonic anhydrase 12	Reversible hydration of carbon dioxide.
WNT10A	Protein Wnt-10a	Ligand for members of the frizzled family of seven transmembrane receptors.
LZTS1	Leucine zipper putative tumor suppressor 1	Involved in the regulation of cell growth.
PMEPA1	Protein TMEPAI	Functions as a negative regulator of TGF-beta signaling and thereby probably plays a role in cell proliferation, differentiation, apoptosis, motility, extracellular matrix production and immunosuppression.
LPAR3	Lysophosphatidic acid receptor 3	Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities.
ACP4	Testicular acid phosphatase	May dephosphorylate receptor tyrosine-protein kinase ERBB4 and inhibits its ligand-induced proteolytic cleavage.
SNX7	Sorting nexin-7	Involved in the regulation of endocytosis and in several stages of intracellular trafficking.
SNX10	Sorting nexin-10	Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes.
ARHGEF16	Rho guanine nucleotide exchange factor 16	Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP.
CGRRF1	Cell growth regulator with RING finger domain protein 1	Able to inhibit growth in several cell lines.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
CHST8	Carbohydrate sulfotransferase 8	Catalyzes the transfer of sulfate to position 4 of non-reducing N-acetylgalactosamine (GalNAc) residues in both N-glycans and O-glycans.
CD1A	T-cell surface glycoprotein CD1a	Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.
CD1C	T-cell surface glycoprotein CD1c	Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.
CD1D	Antigen-presenting glycoprotein CD1d	Antigen-presenting protein that binds self and non-self glycolipids and presents them to T-cell receptors on natural killer T-cells.
NOD1	Nucleotide-binding oligomerization domain-containing protein 1	Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and thus participates in both innate and adaptive immune responses.
CD33	Myeloid cell surface antigen CD33	Sialic-acid-binding immunoglobulin-like lectin (Siglec) that plays a role in mediating cell-cell interactions and in maintaining immune cells in a resting state.
BOC	Brother of CDO	Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells.
ALLC	Probable inactive allantoicase	The function of this enzyme is unclear as allantoicase activity is not known to exist in mammals.
CDH13	Cadherin-13	Cadherins are calcium-dependent cell adhesion proteins.
CDH9	Cadherin-9	Cadherins are calcium-dependent cell adhesion proteins.
LIN7A	Protein lin-7 homolog A	Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells.
RHOU	Rho-related GTP-binding protein RhoU	Binds to and activates protein kinase PAK1.
CDKN3	Cyclin-dependent kinase inhibitor 3	May play a role in cell cycle regulation.
GRHL1	Grainyhead-like protein 1 homolog	Transcription factor involved in epithelial development.
RHCG	Ammonium transporter Rh type C	Ammonium transporter involved in the maintenance of acid-base homeostasis.
FKBP14	Peptidyl-prolyl cis-trans isomerase FKBP14	PPIase which accelerates the folding of proteins during protein synthesis.
KCNH8	Voltage-gated delayed rectifier potassium channel KCNH8	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents.

Protein-family classification

Druggable: 20 · Difficult: 16 · Unknown: 39 · 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
Ion channel	3	4.5×	0.239
Antibody/Immunoglobulin	6	2.3×	0.239
Phosphatase	2	2.2×	0.815
Transcription factor	11	1.2×	0.815
Scaffold/PPI	5	1.1×	0.937
Kinase	3	1.1×	0.937
Transporter	1	1.0×	0.963
Other/Unknown	39	0.9×	0.963
GPCR	2	0.6×	0.963
Protease	1	0.5×	0.963
Enzyme (other)	2	0.3×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS6KA2	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
SALL1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sal_C2H2-zinc-finger
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SIGLEC9	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
SLC25A10	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
NHERF1	Scaffold/PPI	no		PDZ, EBP50_C, NHERF-1/NHERF-2
TAF1B	Transcription factor	no		TF_Rrn7_Zf, TAF1B/Rrn7, Rrn7_cyclin_C
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
MPPED2	Other/Unknown	no		Calcineurin-like_PHP, Calcineurin-like_Pesterase, Metallo-depent_PP-like
KLF11	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
TRPM2	Ion channel	yes		NUDIX_hydrolase_dom, Ion_trans_dom, NUDIX_hydrolase-like_dom_sf
TWSG1	Other/Unknown	no		Tsg, Tsg_N, Tsg_C
TSPEAR	Other/Unknown	no		EPTP, EAR, ConA-like_dom_sf
ZRANB2	Transcription factor	no		Znf_RanBP2, ZRANB2, Znf_RanBP2_sf
SIRAL2	Other/Unknown	no		FAM118
ZNF98	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
LGR4	GPCR	yes		GPCR_Rhodpsn, LRRNT, Leu-rich_rpt
MEPE	Other/Unknown	no		MEPE
PHTF2	Other/Unknown	no		PHTF1/2_N, PHTF1/2
RBMS3	Other/Unknown	no		RRM_dom, Hud_Sxl_RNA, Nucleotide-bd_a/b_plait_sf
TRAF3IP2	Other/Unknown	no		SEFIR_dom, E3_ubiq_ligase_TRAF3IP2
MAML1	Other/Unknown	no		Mastermind-like_N, MAML1-3, MAML_N_sf
CA12	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
DMRTA1	Other/Unknown	no		DM_DNA-bd, DMA, UBA-like_sf
WNT10A	Other/Unknown	no		Wnt, Wnt10, Wnt_CS
LZTS1	Other/Unknown	no		LZTS
PMEPA1	Other/Unknown	no		TMEPAI/LRAD4
LPAR3	GPCR	yes		GPCR_Rhodpsn, LPA_rcpt, LPA_rcpt_EDG7
IRX2	Transcription factor	no		HD, Iroquois_homeo, KN_HD
ACP4	Phosphatase	yes		His_Pase_clade-2, His_PPase_superfam, Acid_Pase_AS
SNX7	Scaffold/PPI	no		PX_dom, AH/BAR_dom_sf, PX_dom_sf
SNX10	Other/Unknown	no		PX_dom, PX_dom_sf, SNX10/11
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
CGRRF1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, CGRF1
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
CHST8	Other/Unknown	no		Sulfotransferase, Carb_sulfotrans_8-10
CD1A	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog
CD1C	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog
CD1D	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog
NOD1	Other/Unknown	no		CARD, Leu-rich_rpt, NACHT_NTPase
MAP3K7CL	Other/Unknown	no		Map3k7cl
CD33	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
BOC	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ALLC	Other/Unknown	no		Allantoicase, Galactose-bd-like_sf, Allantoicase_dom
CDH13	Other/Unknown	no		Cadherin-like_dom, Cadherin_pro_dom, Cadherin-like_sf
CDH9	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
LIN7A	Scaffold/PPI	no		PDZ, L27_dom, L27_C
RHOU	Other/Unknown	no		Small_GTPase, Small_GTPase_Rho, Small_GTP-bd

Expression context

Cohort genes with no expression data: 0.

71 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
male germ line stem cell (sensu Vertebrata) in testis	7
primordial germ cell in gonad	7
sural nerve	6
cartilage tissue	6
leukocyte	5
monocyte	5
tibia	5
ventricular zone	4
mononuclear cell	4
lower esophagus mucosa	4
ganglionic eminence	4
right testis	4
bronchial epithelial cell	4
endothelial cell	4
corpus callosum	4
lower lobe of lung	3
renal medulla	3
pigmented layer of retina	3
right lobe of liver	3
oocyte	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS6KA2	295	ubiquitous	marker	inferior olivary complex, lower lobe of lung, medial globus pallidus
SALL1	195	broad	marker	ventricular zone, inferior vagus X ganglion, renal medulla
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
SIGLEC9	162	broad	marker	monocyte, mononuclear cell, leukocyte
SLC25A10	133	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, liver
NHERF1	284	ubiquitous	marker	granulocyte, lower esophagus mucosa, esophagus mucosa
TAF1B	256	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, adrenal tissue
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
MPPED2	255	broad	marker	ventricular zone, ganglionic eminence, cortical plate
KLF11	260	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
TRPM2	176	broad	marker	right frontal lobe, caudate nucleus, nucleus accumbens
TWSG1	279	ubiquitous	marker	seminal vesicle, cartilage tissue, germinal epithelium of ovary
TSPEAR	88	tissue_specific	yes	primordial germ cell in gonad, adenohypophysis, pituitary gland
ZRANB2	266	ubiquitous	marker	epithelial cell of pancreas, oviduct epithelium, ileal mucosa
SIRAL2	239	ubiquitous	marker	right testis, left testis, gall bladder
ZNF98	128	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, body of pancreas
LGR4	280	ubiquitous	marker	adrenal tissue, body of pancreas, hair follicle
MEPE	52	tissue_specific	marker	tibia, periodontal ligament, trabecular bone tissue
PHTF2	289	ubiquitous	marker	tibia, skeletal muscle tissue of rectus abdominis, biceps brachii
RBMS3	268	ubiquitous	marker	trigeminal ganglion, pericardium, calcaneal tendon
TRAF3IP2	266	ubiquitous	marker	cartilage tissue, oocyte, skin of leg
MAML1	223	ubiquitous	marker	sural nerve, ventricular zone, ganglionic eminence
CA12	260	ubiquitous	marker	renal medulla, nephron tubule, cervix squamous epithelium
DMRTA1	131	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, islet of Langerhans
WNT10A	151	broad	marker	primordial germ cell in gonad, lower esophagus mucosa, bone marrow cell
LZTS1	200	broad	marker	cortical plate, ganglionic eminence, nucleus accumbens
PMEPA1	277	ubiquitous	marker	visceral pleura, ascending aorta, thoracic aorta
LPAR3	170	broad	marker	bronchial epithelial cell, right uterine tube, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFBR1	4,828
BMP4	4,425
RHOU	3,874
ACAD9	3,600
CDKN3	3,381
MED12	3,322
IFT88	3,166
CD33	2,762
NHERF1	2,599
LGR4	2,525

Intra-cohort edges

A	B	Sources
BMP4	TWSG1	biogrid_interaction, string_interaction
BOC	SIGLEC9	intact
CD33	SIGLEC9	intact
CD33	THSD7A	biogrid_interaction, intact
CGRRF1	CNIH1	string_interaction
CHST8	CHST9	intact
GRHL1	KLF11	string_interaction
GRHL1	SALL1	intact
KLF11	RPS6KA2	intact
PMEPA1	TGFBR1	string_interaction
TRPM2	TSPEAR	string_interaction

Structural data

PDB: 36 · AlphaFold-only: 38 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
SCN9A	Q15858	43
CA12	O43570	40
LGR4	Q9BXB1	23
NHERF1	O14745	22
CD1D	P15813	22
CD1A	P06126	16
TRPM2	O94759	15
CD1C	P29017	10
CD33	P20138	10
AAK1	Q2M2I8	8
TWSG1	Q9GZX9	6
NOD1	Q9Y239	6
CHRNA3	P32297	5
MAML1	Q92585	4
MED12	Q93074	3
ZRANB2	O95218	3
SNX10	Q9Y5X0	3
RTEL1	Q9NZ71	3
BOC	Q9BWV1	3
GRHL1	Q9NZI5	3
NLRP5	P59047	3
CDKN3	Q16667	2
FKBP14	Q9NWM8	2
RUFY1	Q96T51	2
ACAD9	Q9H845	2
TRAF3IP2	O43734	1
LZTS1	Q9Y250	1
SNX7	Q9UNH6	1
ARHGEF16	Q5VV41	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPPED2	Q15777	95.43
ALLC	Q8N6M5	91.83
NT5DC1	Q5TFE4	88.76
ACP4	Q9BZG2	88.30
TSPEAR	Q8WU66	87.47
MAP3K7CL	P57077	85.09
WSB1	Q9Y6I7	84.61
SIRAL2	Q9NWS6	83.77
WNT10A	Q9GZT5	82.36
LPAR3	Q9UBY5	81.63
HS6ST3	Q8IZP7	81.20
LIN7A	O14910	80.84
CHST8	Q9H2A9	79.90
CLDN10	P78369	79.61
TAF1B	Q53T94	79.35
BMP4	P12644	79.12
CHST9	Q7L1S5	78.39
CDH9	Q9ULB4	77.60
SLC25A10	Q9UBX3	77.53
RPS6KA2	Q15349	77.37
IFT88	Q13099	77.20
SIGLEC9	Q9Y336	74.10
ZNF98	A6NK75	72.72
ADAMTS3	O15072	71.31
KCNH8	Q96L42	64.41
RBMS3	Q6XE24	63.30
PHTF2	Q8N3S3	60.23
DMRTA1	Q5VZB9	57.14
PMEPA1	Q969W9	57.03
IRX2	Q9BZI1	55.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 540. Enrichment computed across 196 evidence-associated genes (124 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 124 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alpha-defensins	4	33.5×	0.002	DEFA1, DEFA4, DEFA6, DEFA1B
Downregulation of TGF-beta receptor signaling	4	13.2×	0.040	TGFBR1, PMEPA1, SMAD3, SMAD7
Defensins	5	9.6×	0.040	DEFA1, DEFA4, DEFA6, DEFB1, DEFA1B
Kidney development	3	19.7×	0.056	SALL1, BMP4, IRX2
Loss of Function of TGFBR1 in Cancer	2	36.8×	0.071	TGFBR1, SMAD3
Loss of Function of SMAD2/3 in Cancer	2	30.7×	0.071	TGFBR1, SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	2	30.7×	0.071	TGFBR1, SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	2	30.7×	0.071	TGFBR1, SMAD3
TGFBR1 KD Mutants in Cancer	2	30.7×	0.071	TGFBR1, SMAD3
Activation of GABAB receptors	3	14.5×	0.071	ADCY3, KCNJ2, KCNJ3
NOTCH4 Intracellular Domain Regulates Transcription	3	13.8×	0.071	MAML1, HES1, SMAD3
GABA B receptor activation	3	13.2×	0.071	ADCY3, KCNJ2, KCNJ3
Neurotransmitter receptors and postsynaptic signal transmission	6	4.8×	0.071	RPS6KA2, LIN7A, CHRNA3, ADCY3, KCNJ2, KCNJ3
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	26.3×	0.091	BOC, PTCH1
Organic anion transport by SLC5/17/25 transporters	2	23.0×	0.094	SLC25A10, SLC5A12
Ligand-receptor interactions	2	23.0×	0.094	BOC, PTCH1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	6	4.2×	0.094	SIGLEC9, CD1A, CD1C, CD1D, CD33, CD300E
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	6	4.2×	0.094	BMP4, MEPE, DMP1, PDIA6, IGF1, KLK1
Myogenesis	3	9.2×	0.111	BOC, MEF2A, NEO1
Class B/2 (Secretin family receptors)	4	6.1×	0.111	WNT10A, CRHBP, FZD1, PTCH1
G protein gated Potassium channels	2	18.4×	0.122	KCNJ2, KCNJ3
SHC-related events triggered by IGF1R	2	18.4×	0.122	IGF1, IGF1R
IRS-related events triggered by IGF1R	2	16.7×	0.136	IGF1, IGF1R
Transmission across Chemical Synapses	6	3.7×	0.136	RPS6KA2, LIN7A, CHRNA3, ADCY3, KCNJ2, KCNJ3
TGF-beta receptor signaling activates SMADs	3	7.9×	0.137	TGFBR1, SMAD3, SMAD7
NOTCH2 intracellular domain regulates transcription	2	15.3×	0.139	MAML1, HES1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	2	15.3×	0.139	IGF1, IGF1R
GABA receptor activation	3	7.7×	0.139	ADCY3, KCNJ2, KCNJ3
Drug resistance of ALK mutants	1	92.1×	0.155	ALK
ASP-3026-resistant ALK mutants	1	92.1×	0.155	ALK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 171 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ureteric bud development	7	18.6×	1e-04	SALL1, BMP4, CRLF1, SMAD3, SMAD6, SMAD7, RARB
disruption of plasma membrane integrity in another organism	4	49.3×	6e-04	DEFA1, DEFA4, DEFA6, DEFA1B
negative regulation of cell population proliferation	16	3.9×	0.002	RPS6KA2, BMP4, NHERF1, KLF11, CGRRF1, CD33, CDH13, CDKN3 (+8 more)
antigen processing and presentation, endogenous lipid antigen via MHC class Ib	3	59.1×	0.004	CD1A, CD1C, CD1D
heart development	11	5.1×	0.004	RPS6KA2, SALL1, TGFBR1, MED12, TRAF3IP2, FOXL1, IRX4, ISL1 (+3 more)
antigen processing and presentation, exogenous lipid antigen via MHC class Ib	3	42.2×	0.009	CD1A, CD1C, CD1D
proteoglycan biosynthetic process	4	19.7×	0.010	CHST8, CHST9, FOXL1, IGF1
signal transduction	25	2.4×	0.012	RPS6KA2, TGFBR1, TSPEAR, NOD1, CD33, RHOU, CNIH1, CHRNA3 (+17 more)
peptidyl-tyrosine autophosphorylation	3	32.9×	0.012	ALK, IGF1R, PTK2B
positive regulation of SMAD protein signal transduction	5	11.2×	0.012	BMP4, TGFBR1, TWSG1, SH2B1, SMAD3
positive regulation of epithelial cell proliferation	6	8.6×	0.012	BMP4, EGFR, FGF10, IGF1, MAP2K5, NR4A3
positive regulation of white fat cell proliferation	2	98.5×	0.013	VSTM2A, FGF10
pharyngeal arch artery morphogenesis	3	29.6×	0.013	BMP4, EDNRA, HES1
outflow tract septum morphogenesis	4	15.2×	0.013	BMP4, ISL1, SMAD6, RARB
pituitary gland development	4	15.2×	0.013	SALL1, BMP4, FGF10, ISL1
biomineral tissue development	4	15.2×	0.013	MEPE, DMP1, DSPP, KLK4
positive regulation of gene expression	14	3.2×	0.014	RPS6KA2, BMP4, TGFBR1, RBMS3, WNT10A, ZNF804A, VSTM2A, EPHX2 (+6 more)
antibacterial humoral response	5	9.7×	0.014	DEFA1, DEFA4, DEFA6, DEFB1, DEFA1B
negative regulation of smooth muscle cell apoptotic process	3	24.6×	0.016	IGF1, MAP2K5, NR4A3
cellular response to calcium ion	6	7.0×	0.016	TRPM2, CRHBP, ITPKB, MEF2A, PKD2, PLCG2
positive regulation of transcription by RNA polymerase II	25	2.2×	0.016	SALL1, BMP4, MED12, MAML1, CDH13, GRHL1, MAMSTR, ZNF827 (+17 more)
metanephric nephron tubule morphogenesis	2	65.7×	0.022	LGR4, HES1
positive regulation of DNA binding	3	21.1×	0.024	PYHIN1, HES1, IGF1
regulation of secondary heart field cardioblast proliferation	2	49.3×	0.031	HES1, ISL1
intracellular monoatomic ion homeostasis	2	49.3×	0.031	RHCG, P2RY2
response to laminar fluid shear stress	2	49.3×	0.031	SMAD6, SMAD7
prostatic bud formation	2	49.3×	0.031	BMP4, FGF10
glomerulus vasculature development	2	49.3×	0.031	ANGPT2, HES1
positive regulation of BMP signaling pathway	4	10.7×	0.031	BMP4, TWSG1, HES1, NEO1
defense response to fungus	4	10.4×	0.031	DEFA1, DEFA4, DEFA6, DEFA1B

Therapeutics

Drugs indicated for this disease

3 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sodium Fluoride	Approved (phase 4)
Sodium Monofluorophosphate	Approved (phase 4)
Stannous Fluoride	Approved (phase 4)
Arginine	Phase 3 (in late-stage trials)
Chlorhexidine	Phase 3 (in late-stage trials)
Cinnamon	Phase 3 (in late-stage trials)
Ginger	Phase 3 (in late-stage trials)
Povidone-Iodine	Phase 3 (in late-stage trials)
Silver	Phase 3 (in late-stage trials)
Silver Diammine Fluoride	Phase 3 (in late-stage trials)
Silver Nitrate	Phase 3 (in late-stage trials)
Xylitol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Aloe, Calcium, Calcium Phosphate, Tribasic, Licorice, Propolis Wax.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 12 · Undrugged: 63

Druggability breadth: 69 of 196 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
RPS6KA2	FEDRATINIB
SCN9A	IMIPRAMINE
TGFBR1	MOMELOTINIB
TRPM2	CLOTRIMAZOLE
CA12	METHAZOLAMIDE
NOD1	GEFITINIB
CHRNA3	VARENICLINE
AAK1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CA12	67	4
AAK1	59	4
SCN9A	36	4
RPS6KA2	29	4
TGFBR1	28	4
CHRNA3	21	4
TRPM2	5	4
TAF1B	1	2
MED12	1	2
ZRANB2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	AAK1, RPS6KA2
RUXOLITINIB	4	AAK1, RPS6KA2
NERATINIB	4	RPS6KA2
TOFACITINIB CITRATE	4	RPS6KA2
TOFACITINIB	4	RPS6KA2
BOSUTINIB	4	AAK1, RPS6KA2
BRIGATINIB	4	RPS6KA2
NINTEDANIB	4	AAK1, RPS6KA2, TGFBR1
SUNITINIB	4	AAK1, RPS6KA2
MIDOSTAURIN	4	AAK1, RPS6KA2
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	CA12, SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
CA12	530	Binding:526, ADMET:4
RPS6KA2	448	Binding:446, ADMET:1, Functional:1
CHRNA3	436	Binding:343, Functional:91, ADMET:2
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
AAK1	216	Binding:216
NOD1	111	Binding:100, Functional:11
LPAR3	74	Functional:56, Binding:18
TRPM2	59	Binding:58, Functional:1
KCNH8	21	Binding:20, Toxicity:1
CD1D	16	Binding:16
NT5DC1	11	Binding:11
ZRANB2	7	Binding:7
TAF1B	6	Binding:6
MED12	6	Binding:6
NHERF1	5	Binding:5
SIGLEC9	3	Binding:3
BMP4	2	Binding:2
LGR4	2	Binding:2
FKBP14	1	Binding:1
ACAD9	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPS6KA2	2.7.11.1	non-specific serine/threonine protein kinase
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
CA12	4.2.1.1	carbonic anhydrase
FKBP14	5.2.1.8	peptidylprolyl isomerase
ADAMTS3	3.4.24.14	procollagen N-endopeptidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RPS6KA2	448
SCN9A	428
TGFBR1	541
CA12	530
NOD1	111
CHRNA3	436
AAK1	216

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; 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)
FEDRATINIB	4	AAK1, RPS6KA2
RUXOLITINIB	4	AAK1, RPS6KA2
NERATINIB	4	RPS6KA2
TOFACITINIB CITRATE	4	RPS6KA2
TOFACITINIB	4	RPS6KA2
BOSUTINIB	4	AAK1, RPS6KA2
BRIGATINIB	4	RPS6KA2
NINTEDANIB	4	AAK1, RPS6KA2, TGFBR1
SUNITINIB	4	AAK1, RPS6KA2
MIDOSTAURIN	4	AAK1, RPS6KA2
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	CA12, SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	RPS6KA2, SCN9A, TGFBR1, TRPM2, CA12, NOD1, CHRNA3, AAK1
B	Phased (≥1) drug, not yet approved	4	TAF1B, MED12, ZRANB2, FKBP14
C	Druggable family + PDB, no drug	7	LGR4, CD1A, CD1C, CD1D, CD33, BOC, CDKN3
D	Druggable family + AlphaFold only, no drug	6	SIGLEC9, SLC25A10, LPAR3, ACP4, KCNH8, ADAMTS3
E	Difficult family or no structure, no drug	50	SALL1, BMP4, NHERF1, MPPED2, KLF11, TWSG1, TSPEAR, SIRAL2, ZNF98, MEPE (+40 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SALL1	0	—
BMP4	2	—
SIGLEC9	3	—
SLC25A10	0	—
NHERF1	5	—
MPPED2	0	—
KLF11	0	—
TWSG1	0	—
TSPEAR	0	—
SIRAL2	0	—
ZNF98	0	—
LGR4	2	—
MEPE	0	—
PHTF2	0	—
RBMS3	0	—
TRAF3IP2	0	—
MAML1	0	—
DMRTA1	0	—
WNT10A	0	—
LZTS1	0	—
PMEPA1	0	—
LPAR3	74	—
IRX2	0	—
ACP4	0	—
SNX7	0	—
SNX10	0	—
ARHGEF16	0	—
CGRRF1	0	—
RTEL1	0	—
CHST8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 655.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	517
PHASE2	33
PHASE4	32
PHASE3	31
PHASE1	17
PHASE2/PHASE3	12
EARLY_PHASE1	10
PHASE1/PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06172764	PHASE4	RECRUITING	A Randomized Controlled Trial of Vitamin D Supplementation on Salivary Biomarkers and Cariogenic Oral Microbiome
NCT06699199	PHASE4	RECRUITING	Effect of Silver Diamine Fluoride Application on Oral Microbiome of Healthy Pediatric Patient
NCT07194629	PHASE4	NOT_YET_RECRUITING	Pilot and Feasibility Study of Impact of SDF 38% Application on Oral Health of Elderly With Autonomy Loss
NCT00268138	PHASE4	UNKNOWN	Elmex Gel Efficacy in Preventing White Spot Lesions
NCT00638677	PHASE4	COMPLETED	Bifidobacterium Lactis BB12 and Xylitol Delivered With a Novel Slow-release Pacifier
NCT00723515	PHASE4	COMPLETED	Therapeutic Effect of Two Fluoride Varnishes on White Spot Lesions: a Clinical Study
NCT00902395	PHASE4	COMPLETED	Efficacy of Moderate Sedation for Dental Treatment of Young Children
NCT01128946	PHASE4	COMPLETED	Enamel Remineralization Potential of Dentifrices in Situ
NCT01142440	PHASE4	UNKNOWN	Dental Caries Management by Risk Assessment: Identification and Treatment of Risk Factors Among (IDF) Personnel
NCT01438866	PHASE4	COMPLETED	Use of Fissure Sealants on Primary Molars
NCT01563172	PHASE4	COMPLETED	Effect of Dentifrice Usage Regime on Delivery and Efficacy of Fluoride
NCT01567514	PHASE4	COMPLETED	Postoperative Pulpal Complications in Posterior Resin Composite Restorations Without Glass-ionomer Cement Lining
NCT01674933	PHASE4	COMPLETED	Fluoride Varnish For Childsmile Nursery School Attenders
NCT01768390	PHASE4	COMPLETED	Caries-preventive Effect of a Dentifrice Containing 5,000 Ppm Fluoride in Orthodontic Patients
NCT01778699	PHASE4	UNKNOWN	Anticaries Effect of Probiotic Lactobacillus Brevis CD2 (Lb CD2).
NCT02338180	PHASE4	COMPLETED	Preventive and Therapeutic Proximal Sealants
NCT02424097	PHASE4	COMPLETED	MI Varnish and MI Paste Plus in a Caries Prevention and Remineralization Study
NCT02447289	PHASE4	COMPLETED	Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment
NCT02490592	PHASE4	COMPLETED	Comparison of the Effect of Fluoride Remineralizer Gel and Foam
NCT02592278	PHASE4	COMPLETED	Prevention of Dental Caries Lesions With Fluoride Varnish in Erupting First Permanent Molars
NCT02692625	PHASE4	UNKNOWN	Consumption Effect of Probiotic Products on Salivary Cariogenic Bacterial Counts in Preschool Children.
NCT02795728	PHASE4	COMPLETED	Fuji Type VII Sealant Versus Resin Based Sealant. A Clinical Trial
NCT02921165	PHASE4	COMPLETED	Comparison of Topical Analgesic With Saline Rinses in Post Extraction Healing
NCT02935322	PHASE4	COMPLETED	Interaction Between Chlorhexidine and Fluoride
NCT03455621	PHASE4	COMPLETED	Effect of the Amount of Fluoride Toothpaste on Fluoride Availability in the Oral Fluids in Children
NCT03770871	PHASE4	COMPLETED	Indirect Pulp Treatment in Primary Molars
NCT03779698	PHASE4	COMPLETED	BiodentineTM Versus Formocresol Pulpotomy Technique in Primary Molars
NCT03881020	PHASE4	COMPLETED	Comparison of Silver Modified and Conventional Atraumatic Restorative Treatment Modalities
NCT04777968	PHASE4	COMPLETED	Evaluation Of Fluoride Uptake By Dentine Following Silver Diamine Fluoride Under Resin Modified Glass Ionomer Restoration In Carious Primary Molars
NCT05772039	PHASE4	UNKNOWN	Treatment of Early Childhood Caries Using Silver Diammine Fluoride and Sodium Fluoride Tricalciumphosphate and the Effects on Oral Health Related Quality of Life
NCT07023939	PHASE4	COMPLETED	Atraumatic Versus Silver-Modified Atraumatic Restorative Treatment in Primary Molars
NCT07579403	PHASE4	COMPLETED	Fluoride vs Probiotic Toothpaste for Caries Prevention
NCT06511336	PHASE3	ACTIVE_NOT_RECRUITING	Alkaline Water and Salivary Bacterial Count
NCT07124533	PHASE3	NOT_YET_RECRUITING	Effectiveness of Toothpaste Tablets on Plaque, Gingival Health and Caries Experiences
NCT07188142	PHASE2/PHASE3	NOT_YET_RECRUITING	Gluma Compared With Bonding Agent for Post-operative Sensitivity Following Composite Restorations
NCT07265830	PHASE3	NOT_YET_RECRUITING	Building Adaptive School-based Interventions for Caries
NCT00065988	PHASE3	COMPLETED	The Children’s Amalgam Trial
NCT00066950	PHASE3	COMPLETED	Prevention Management Model for Early Childhood Caries (MAYA Project)
NCT00066963	PHASE3	COMPLETED	Fluoride Varnish Randomized Clinical Trial
NCT00067340	PHASE3	TERMINATED	Caries Transmission Prevention in Alaska Native Infants

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHLORHEXIDINE	4	12
SODIUM FLUORIDE	4	11
KETAMINE	4	2
BROMELAINS	4	1
CALCIUM	4	1
FERUMOXYTOL	4	1
HYDROGEN PEROXIDE	4	1
MIDAZOLAM	4	1
NYSTATIN	4	1
SALICYLIC ACID	4	1
SILVER NITRATE	4	1
SODIUM HYPOCHLORITE	4	1
SODIUM IODIDE	4	1
SORBITOL	4	1
URETHANE	4	1
VANCOMYCIN	4	1
WATER	4	1
FLUORIDE ION	3	27
SILVER DIAMMINE FLUORIDE	3	22
XYLITOL	3	8
SILVER	3	3
POWDERED CELLULOSE	3	2
ARTEMISININ	3	1
CINNAMON	3	1
FERRIC SULFATE	3	1
GINGER	3	1
LICORICE	3	1
LITHIUM	3	1
OZONE	3	1
PARAFFIN	3	1