Testicular germ cell tumor

Summary

Testicular germ cell tumor (MONDO:0010108) is a cancer (an umbrella term covering 6 Mondo subtypes) with 75 cohort genes (94 GWAS associations across 5 studies; 9 CIViC-evidence somatic drivers; 122 ClinVar predisposition records) and 87 clinical trials. The dominant Reactome pathway is Constitutive Signaling by Aberrant PI3K in Cancer (5 cohort genes). Top therapeutic interventions include ifosfamide, bleomycin sulfate, and cyclophosphamide anhydrous.

At a glance

• Classification: Cancer
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 94
• ClinVar variants: 122
• Clinical trials: 87

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	testicular germ cell tumor
Mondo ID	MONDO:0010108
EFO	EFO:1000566
MeSH	C563236
OMIM	273300
Orphanet	363504
DOID	DOID:5557
NCIT	C8591
SNOMED CT	713577007
UMLS	C1336708
MedGen	277809
GARD	0013047
Anatomy (UBERON)	UBERON:0000473
Is cancer (heuristic)	yes

Also known as: endodermal sinus tumour · germ cell neoplasm of testis · germ cell neoplasm of the testis · germ cell tumor of testis · germ cell tumor of the testis · germ cell tumors, somatic · germ cell tumour of testis · germ cell tumour of the testis · male germ cell tumor, somatic · Male germ cell tumour · nonseminomatous germ cell tumours · spermatocytic seminoma, somatic · testicular germ cell neoplasm · testicular germ cell neoplasms · testicular germ cell tumor · testicular tumor, somatic · testis germ cell tumor · testis germ cell tumour · TGCT

Data availability: 122 ClinVar variants · 94 GWAS associations (5 studies) · 2 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › germ cell tumor › gonadal germ cell tumor › testicular germ cell tumor

Related subtypes (2): malignant germ cell tumor of ovary, childhood gonadal germ cell tumor

Subtypes (6): testicular pure germ cell tumor, malignant testicular germ cell tumor, childhood testicular germ cell tumor, testicular non-seminomatous germ cell tumor, testicular germ cell tumor 1, testicular teratoma

Genetics & variants

GWAS landscape

94 GWAS associations across 5 studies. Top hits map to 40 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3782181	3e-129	KITLG	C	2.07
rs4624820	3e-57	NDFIP1 - SPRY4	G	1.47
rs7040024	2e-45	DMRT1	A	1.53
rs755383	7e-41	DMRT1	T	1.49
rs210138	4e-37	BAK1	G	1.48
rs4635969	3e-27	TERT - MIR4457	A	1.46
rs2736100	9e-25	TERT	A	1.28
rs55873183	2e-23	DMRT1	G	1.89
rs7501939	3e-20	HNF1B	T	1.25
rs9905704	3e-20	SEPTIN4-AS1	G	1.27
rs2720460	7e-20	CENPE	A	1.26
rs2241024	1e-16	LINC00662	G	1.23
rs3790672	2e-14	UCK2	C	1.27
rs58521262	5e-14	LINC01859	G	1.35
rs4240895	6e-13	PIK3CD, PIK3CD-AS1	T	1.14
rs12699477	6e-13	MAD1L1	C	1.2
rs11071896	8e-13	ZWILCH	G	1.19
rs7404843	8e-13	BMERB1	G	1.28
rs2900333	9e-13	ATF7IP	C	1.2
rs4862848	2e-12	ZFP42	G	1.21
rs648090	2e-12	PKNOX2	A	1.15
rs1510272	2e-12	SSR3 - TIPARP-AS1	C	1.23
rs12481572	3e-12	ZFP64	T	1.2
rs4888262	7e-12	RFWD3	?	1.18
rs2839186	7e-12	MCM3AP, MCM3AP-AS1	T	1.18
rs12912292	1e-11	PRTG - NEDD4	A	1.22
rs4931000	2e-11	RESF1	G	1.16
rs7581030	2e-11	ZNF638	T	1.17
rs6821144	2e-11	CDKL2	G	1.22
rs34601376	2e-11	RPSA2	T	1.29

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004635	Litchfield K	2017	5,518	19,055	Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.
GCST004713	Wang Z	2017	3,558	13,970	Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor.
GCST002855	Kristiansen W	2015	1,326	6,687	Two new loci and gene sets related to sex determination and cancer progression are associated with susceptibility to testicular germ cell tumor.
GCST003246	Litchfield K	2015	986	4,946	Identification of four new susceptibility loci for testicular germ cell tumour.
GCST003247	Litchfield K	2015	986	4,946	Identification of four new susceptibility loci for testicular germ cell tumour.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	46

MAF distribution

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

Functional consequences

Consequence	Count
intron_variant	34
intergenic_variant	10
non_coding_transcript_exon_variant	1
missense_variant	1
3_prime_UTR_variant	1
regulatory_region_variant	1
synonymous_variant	1
splice_polypyrimidine_tract_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3782181	12	88559784	C>A	0.19	intron_variant	KITLG	3e-129	Tier 4: intronic/intergenic
rs4624820	5	142302223	G>A	0.44	intergenic_variant	NDFIP1 - SPRY4	3e-57	Tier 4: intronic/intergenic
rs7040024	9	845516	A>C,G,T	0.23	intron_variant	DMRT1	2e-45	Tier 4: intronic/intergenic
rs755383	9	863635	C>A,T	0.39	intron_variant	DMRT1	7e-41	Tier 4: intronic/intergenic
rs210138	6	33574761	A>C,G,T	0.21	intron_variant	BAK1	4e-37	Tier 4: intronic/intergenic
rs4635969	5	1308437	G>A,C,T	0.2	intergenic_variant	TERT - MIR4457	3e-27	Tier 4: intronic/intergenic
rs2736100	5	1286401	C>A,G,T	0.49	intron_variant	TERT	9e-25	Tier 4: intronic/intergenic
rs55873183	9	878563	A>G	0.07	intron_variant	DMRT1	2e-23	Tier 4: intronic/intergenic
rs7501939	17	37741165	C>G,T	0.39	intron_variant	HNF1B	3e-20	Tier 4: intronic/intergenic
rs9905704	17	58555182	G>A,C,T	0.32	intron_variant	SEPTIN4-AS1	3e-20	Tier 4: intronic/intergenic
rs2720460	4	103133529	A>G	0.37	intron_variant	CENPE	7e-20	Tier 4: intronic/intergenic
rs2241024	19	27766485	G>A,C	0.2	intron_variant	LINC00662	1e-16	Tier 4: intronic/intergenic
rs3790672	1	165904155	T>A,C,G	0.28	intron_variant	UCK2	2e-14	Tier 4: intronic/intergenic
rs58521262	19	23022382	G>A	0.173	intron_variant	LINC01859	5e-14	Tier 4: intronic/intergenic
rs4240895	1	9653328	C>A,T	0.39	non_coding_transcript_exon_variant	PIK3CD, PIK3CD-AS1	6e-13	Tier 4: intronic/intergenic
rs12699477	7	1929317	T>A,C,G	0.39	intron_variant	MAD1L1	6e-13	Tier 4: intronic/intergenic
rs11071896	15	66528912	A>G	0.26	missense_variant	ZWILCH	8e-13	Tier 1: coding
rs7404843	16	15436851	T>A,G	0.11	intron_variant	BMERB1	8e-13	Tier 4: intronic/intergenic
rs2900333	12	14500933	C>A,G,T	0.37	3_prime_UTR_variant	ATF7IP	9e-13	Tier 2: splice/UTR
rs4862848	4	188000286	A>C,G,T	0.35	intron_variant	ZFP42	2e-12	Tier 4: intronic/intergenic
rs648090	11	125201267	A>C,G,T	0.29	intron_variant	PKNOX2	2e-12	Tier 4: intronic/intergenic
rs1510272	3	156582935	C>G,T	0.25	regulatory_region_variant	SSR3 - TIPARP-AS1	2e-12	Tier 3: regulatory
rs12481572	20	52091515	A>C,G,T	0.2	intron_variant	ZFP64	3e-12	Tier 4: intronic/intergenic
rs4888262	16	74636560	C>T	0.5	synonymous_variant	RFWD3	7e-12	Tier 4: intronic/intergenic
rs2839186	21	46270154	C>T	0.48	intron_variant	MCM3AP, MCM3AP-AS1	7e-12	Tier 4: intronic/intergenic
rs12912292	15	55746509	G>A,T	0.48	intergenic_variant	PRTG - NEDD4	1e-11	Tier 4: intronic/intergenic
rs4931000	12	31988561	A>G,T	0.22	intron_variant	RESF1	2e-11	Tier 4: intronic/intergenic
rs7581030	2	71345325	C>G,T	0.24	intron_variant	ZNF638	2e-11	Tier 4: intronic/intergenic
rs6821144	4	75595467	G>A	0.11	intron_variant	CDKL2	2e-11	Tier 4: intronic/intergenic
rs34601376	19	23868026	A>T	0.195	intron_variant	RPSA2	2e-11	Tier 4: intronic/intergenic

ClinVar germline variants

122 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 32 conflicting classifications of pathogenicity, 18 benign/likely benign, 14 pathogenic, 5 likely pathogenic, 3 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16331	NM_000142.5(FGFR3):c.1948A>G (p.Lys650Glu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16332	NM_000142.5(FGFR3):c.742C>T (p.Arg248Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16335	NM_000142.5(FGFR3):c.2419T>A (p.Ter807Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16340	NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16341	NM_000142.5(FGFR3):c.1949A>T (p.Lys650Met)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16347	NM_000142.5(FGFR3):c.1950G>C (p.Lys650Asn)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16359	NM_000142.5(FGFR3):c.1108G>T (p.Gly370Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
65562	NM_000142.5(FGFR3):c.2420G>T (p.Ter807Leu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
13863	NM_000222.3(KIT):c.2446G>C (p.Asp816His)	KIT	Pathogenic	criteria provided, multiple submitters, no conflicts
1184620	NM_000455.5(STK11):c.812del (p.Ser271fs)	STK11	Pathogenic	no assertion criteria provided
3383032	NM_000455.5(STK11):c.388dup (p.Glu130fs)	STK11	Pathogenic	criteria provided, multiple submitters, no conflicts
3600336	NM_000455.5(STK11):c.876C>A (p.Tyr292Ter)	STK11	Pathogenic	criteria provided, multiple submitters, no conflicts
3892570	NM_000455.5(STK11):c.147C>G (p.Tyr49Ter)	STK11	Pathogenic	criteria provided, multiple submitters, no conflicts
3892950	NC_000019.9:g.(?1218416)(1222005_?)del	STK11	Pathogenic	criteria provided, single submitter
3892951	NC_000019.9:g.1206913_1219412del	STK11	Pathogenic	criteria provided, single submitter
3892952	NC_000019.9:g.1206913_1226646del	STK11	Pathogenic	criteria provided, single submitter
182898	NM_000455.5(STK11):c.487G>C (p.Gly163Arg)	STK11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
220351	NM_000455.5(STK11):c.923G>T (p.Trp308Leu)	STK11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583467	NM_000455.5(STK11):c.810del (p.Ser271fs)	STK11	Likely pathogenic	criteria provided, single submitter
3892572	NM_000455.5(STK11):c.922T>G (p.Trp308Gly)	STK11	Likely pathogenic	criteria provided, single submitter
3892953	NM_000455.5(STK11):c.292_464+1del	STK11	Likely pathogenic	criteria provided, single submitter
1680106	NM_000142.5(FGFR3):c.1827C>G (p.Ala609=)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287276	NM_000142.5(FGFR3):c.598C>T (p.Arg200Cys)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579912	NM_000142.5(FGFR3):c.2005C>G (p.Arg669Gly)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134627	NM_000222.3(KIT):c.2866C>T (p.Arg956Trp)	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500519	NM_000222.3(KIT):c.1231+13A>T	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225286	NM_000222.3(KIT):c.464C>T (p.Pro155Leu)	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237233	NM_000222.3(KIT):c.1109A>G (p.Asn370Ser)	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409715	NM_000222.3(KIT):c.2920G>A (p.Asp974Asn)	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
409716	NM_000222.3(KIT):c.2848G>A (p.Val950Met)	KIT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 87 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 4

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
TERT	TERT	GWAS, Orphanet
SPRY4	SPRY4	GWAS, Orphanet
KITLG	KITLG	GWAS, Orphanet
MAP2K1	MAP2K1	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
STK11	LoF	ANSC,CEAD,CESC,CHOL,LUAD,NSCLC,WDTC	CIViC #5534
TERT	Act	PRCC	CIViC #79
TNFRSF17			CIViC #570
TYMS			CIViC #5971
ATF7IP	LoF	LUAD,UCEC
FGFR3	Act	BLADDER,BLCA,HNSC,LUSC,PCM,PLMESO,UTUC	CIViC #23
KIT	Act	AML,GIST,MEL,MGCT	CIViC #29
LATS1	LoF	BCC,BRCA,CEAD,CESC,OVT,PAAD
MAP2K1	Act	DLBCLNOS,LUAD,MEL,NSCLC,SKCM	CIViC #31

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STK11	Orphanet:2869	Peutz-Jeghers syndrome
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
TEX14	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
TYMS	Orphanet:1775	Dyskeratosis congenita
SPRY4	Orphanet:363494	Non-seminomatous germ cell tumor of testis
SPRY4	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
SPRY4	Orphanet:478	Kallmann syndrome
SMARCAD1	Orphanet:1658	Absence of fingerprints-congenital milia syndrome
SMARCAD1	Orphanet:289465	Isolated congenital adermatoglyphia
SMARCAD1	Orphanet:384	Huriez syndrome
CENPE	Orphanet:2512	Autosomal recessive primary microcephaly
CENPE	Orphanet:808	Seckel syndrome
CLCN6	Orphanet:610573	CLCN6-related childhood-onset progressive neurodegeneration-peripheral neuropathy syndrome
NLRP12	Orphanet:247868	NLRP12-associated hereditary periodic fever syndrome
RFWD3	Orphanet:84	Fanconi anemia
HEATR3	Orphanet:124	Diamond-Blackfan anemia
DMRT1	Orphanet:242	46,XY complete gonadal dysgenesis
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome
FGFR3	Orphanet:85165	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
FGFR3	Orphanet:93262	Crouzon syndrome-acanthosis nigricans syndrome
FGFR3	Orphanet:93274	Thanatophoric dysplasia type 2
GATA4	Orphanet:251071	8p23.1 microdeletion syndrome
GATA4	Orphanet:251510	46,XY partial gonadal dysgenesis
GATA4	Orphanet:3303	Tetralogy of Fallot

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	72
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC28A1	HGNC:11001	ENSG00000156222	O00337	Sodium/nucleoside cotransporter 1	gwas
SSR3	HGNC:11325	ENSG00000114850	Q9UNL2	Translocon-associated protein subunit gamma	gwas
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gwas
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TEX14	HGNC:11737	ENSG00000121101	Q8IWB6	Inactive serine/threonine-protein kinase TEX14	gwas
TFDP2	HGNC:11751	ENSG00000114126	Q14188	Transcription factor Dp-2	gwas
TKTL1	HGNC:11835	ENSG00000007350	P51854	Transketolase-like protein 1	gwas
TNFRSF17	HGNC:11913	ENSG00000048462	Q02223	Tumor necrosis factor receptor superfamily member 17	gwas
TYMS	HGNC:12441	ENSG00000176890	P04818	Thymidylate synthase	gwas
UCK2	HGNC:12562	ENSG00000143179	Q9BZX2	Uridine-cytidine kinase 2	gwas
ZNF257	HGNC:13498	ENSG00000197134	Q9Y2Q1	Zinc finger protein 257	gwas
PRDM14	HGNC:14001	ENSG00000147596	Q9GZV8	PR domain zinc finger protein 14	gwas
GAB2	HGNC:14458	ENSG00000033327	Q9UQC2	GRB2-associated-binding protein 2	gwas
SPRY4	HGNC:15533	ENSG00000187678	Q9C004	Protein sprouty homolog 4	gwas
MCM3AP-AS1	HGNC:16417	ENSG00000215424		MCM3AP antisense RNA 1	gwas
PKNOX2	HGNC:16714	ENSG00000165495	Q96KN3	Homeobox protein PKNOX2	gwas
DLGAP5	HGNC:16864	ENSG00000126787	Q15398	Disks large-associated protein 5	gwas
CDKL2	HGNC:1782	ENSG00000138769	Q92772	Cyclin-dependent kinase-like 2	gwas
HPGDS	HGNC:17890	ENSG00000163106	O60760	Hematopoietic prostaglandin D synthase	gwas
ZNF638	HGNC:17894	ENSG00000075292	Q14966	Zinc finger protein 638	gwas
TFCP2L1	HGNC:17925	ENSG00000115112	Q9NZI6	Transcription factor CP2-like protein 1	gwas
SMARCAD1	HGNC:18398	ENSG00000163104	Q9H4L7	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1	gwas
CENPE	HGNC:1856	ENSG00000138778	Q02224	Centromere-associated protein E	gwas
ZFPM1	HGNC:19762	ENSG00000179588	Q8IX07	Zinc finger protein ZFPM1	gwas
TBPL2	HGNC:19841	ENSG00000182521	Q6SJ96	TATA box-binding protein-like 2	gwas
ATG14	HGNC:19962	ENSG00000126775	Q6ZNE5	Beclin 1-associated autophagy-related key regulator	gwas
USP35	HGNC:20061	ENSG00000118369	Q9P2H5	Ubiquitin carboxyl-terminal hydrolase 35	gwas
ATF7IP	HGNC:20092	ENSG00000171681	Q6VMQ6	Activating transcription factor 7-interacting protein 1	gwas
FBXO34	HGNC:20201	ENSG00000178974	Q9NWN3	F-box only protein 34	gwas
CLCN6	HGNC:2024	ENSG00000011021	P51797	H(+)/Cl(-) exchange transporter 6	gwas
CATSPER3	HGNC:20819	ENSG00000152705	Q86XQ3	Cation channel sperm-associated protein 3	gwas
CLUL1	HGNC:2096	ENSG00000079101	Q15846	Clusterin-like protein 1	gwas
NCAPG2	HGNC:21904	ENSG00000146918	Q86XI2	Condensin-2 complex subunit G2	gwas
BCAR4	HGNC:22170	ENSG00000262117		breast cancer anti-estrogen resistance 4	gwas
NLRP12	HGNC:22938	ENSG00000142405	P59046	NACHT, LRR and PYD domains-containing protein 12	gwas
GPR160	HGNC:23693	ENSG00000173890	Q9UJ42	Probable G-protein coupled receptor 160	gwas
TIPARP	HGNC:23696	ENSG00000163659	Q7Z3E1	Protein mono-ADP-ribosyltransferase TIPARP	gwas
CLPTM1L	HGNC:24308	ENSG00000049656	Q96KA5	Lipid scramblase CLPTM1L	gwas
RSL1D1	HGNC:24534	ENSG00000171490	O76021	Ribosomal L1 domain-containing protein 1	gwas
RFWD3	HGNC:25539	ENSG00000168411	Q6PCD5	E3 ubiquitin-protein ligase RFWD3	gwas
RESF1	HGNC:25559	ENSG00000174718	Q9HCM1	Retroelement silencing factor 1	gwas
HEATR3	HGNC:26087	ENSG00000155393	Q7Z4Q2	HEAT repeat-containing protein 3	gwas
PLBD1	HGNC:26215	ENSG00000121316	Q6P4A8	Lysosomal leucine aminopeptidase	gwas
PRTG	HGNC:26373	ENSG00000166450	Q2VWP7	Protogenin	gwas
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	gwas
MPV17L	HGNC:26827	ENSG00000156968	Q2QL34	Mpv17-like protein	gwas
DAZL	HGNC:2685	ENSG00000092345	Q92904	Deleted in azoospermia-like	gwas
SLC25A44	HGNC:29036	ENSG00000160785	Q96H78	Solute carrier family 25 member 44	gwas
DMRT1	HGNC:2934	ENSG00000137090	Q9Y5R6	Doublesex- and mab-3-related transcription factor 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC28A1	Sodium/nucleoside cotransporter 1	Sodium and pyrimidine nucleoside symporter of the plasma membrane that imports uridine, thymidine and cytidine into cells by coupling their transport to the transmembrane sodium electrochemical gradient.
SSR3	Translocon-associated protein subunit gamma	TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TEX14	Inactive serine/threonine-protein kinase TEX14	Required both for the formation of intercellular bridges during meiosis and for kinetochore-microtubule attachment during mitosis.
TFDP2	Transcription factor Dp-2	Can stimulate E2F-dependent transcription.
TKTL1	Transketolase-like protein 1	Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate.
TNFRSF17	Tumor necrosis factor receptor superfamily member 17	Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL.
TYMS	Thymidylate synthase	Catalyzes the reductive methylation of 2’-deoxyuridine 5’-monophosphate (dUMP) to thymidine 5’-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to…
UCK2	Uridine-cytidine kinase 2	Phosphorylates uridine and cytidine to uridine monophosphate and cytidine monophosphate.
ZNF257	Zinc finger protein 257	May be involved in transcriptional regulation.
PRDM14	PR domain zinc finger protein 14	Transcription factor that has both positive and negative roles on transcription.
GAB2	GRB2-associated-binding protein 2	Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways.
SPRY4	Protein sprouty homolog 4	Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras.
DLGAP5	Disks large-associated protein 5	Potential cell cycle regulator that may play a role in carcinogenesis of cancer cells.
HPGDS	Hematopoietic prostaglandin D synthase	Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range…
ZNF638	Zinc finger protein 638	Transcription factor that binds to cytidine clusters in double-stranded DNA.
TFCP2L1	Transcription factor CP2-like protein 1	Transcription factor that facilitates establishment and maintenance of pluripotency in embryonic stem cells (ESCs).
SMARCAD1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1	Protein that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization.
CENPE	Centromere-associated protein E	Microtubule plus-end-directed kinetochore motor which plays an important role in chromosome congression, microtubule-kinetochore conjugation and spindle assembly checkpoint activation.
ZFPM1	Zinc finger protein ZFPM1	Transcription regulator that plays an essential role in erythroid and megakaryocytic cell differentiation.
TBPL2	TATA box-binding protein-like 2	Transcription factor required in complex with TAF3 for the differentiation of myoblasts into myocytes.
ATG14	Beclin 1-associated autophagy-related key regulator	Required for both basal and inducible autophagy.
USP35	Ubiquitin carboxyl-terminal hydrolase 35	Deubiquitinase that plays a role in different processes including cell cycle regulation, mitophagy or endoplasmic reticulum stress.
ATF7IP	Activating transcription factor 7-interacting protein 1	Recruiter that couples transcriptional factors to general transcription apparatus and thereby modulates transcription regulation and chromatin formation.
FBXO34	F-box only protein 34	Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex promoting ubiquitination and proteasomal degradation of specific target proteins including HNRNPU.
CLCN6	H(+)/Cl(-) exchange transporter 6	Voltage-gated channel mediating the exchange of chloride ions against protons.
CATSPER3	Cation channel sperm-associated protein 3	Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acros…
NCAPG2	Condensin-2 complex subunit G2	Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis.
NLRP12	NACHT, LRR and PYD domains-containing protein 12	Plays an essential role as an potent mitigator of inflammation.
GPR160	Probable G-protein coupled receptor 160	Orphan receptor.
TIPARP	Protein mono-ADP-ribosyltransferase TIPARP	ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate, aspartate and cysteine residues on target proteins.
CLPTM1L	Lipid scramblase CLPTM1L	Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to th…
RSL1D1	Ribosomal L1 domain-containing protein 1	Regulates cellular senescence through inhibition of PTEN translation.
RFWD3	E3 ubiquitin-protein ligase RFWD3	E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage.
RESF1	Retroelement silencing factor 1	Plays a role in the regulation of imprinted gene expression, regulates repressive epigenetic modifications associated with SETDB1.
HEATR3	HEAT repeat-containing protein 3	Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5).
PLBD1	Lysosomal leucine aminopeptidase	Lysosomal processive monoaminopeptidase that preferentially cleaves hydrophobic amino acids, with strong preference for leucine residues.
PRTG	Protogenin	May play a role in anteroposterior axis elongation.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.
MPV17L	Mpv17-like protein	Participates in reactive oxygen species metabolism by up- or down-regulation of the genes of antioxidant enzymes.
DAZL	Deleted in azoospermia-like	RNA-binding protein, which is essential for gametogenesis in both males and females.
SLC25A44	Solute carrier family 25 member 44	Mitochondrial solute transporter which transports branched-chain amino acid (BCAA; valine, leucine and isoleucine) into mitochondria in brown adipose tissue (BAT).
DMRT1	Doublesex- and mab-3-related transcription factor 1	Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation.
LHPP	Phospholysine phosphohistidine inorganic pyrophosphate phosphatase	Phosphatase that hydrolyzes imidodiphosphate, 3-phosphohistidine and 6-phospholysine.
G3BP2	Ras GTPase-activating protein-binding protein 2	Scaffold protein that plays an essential role in cytoplasmic stress granule formation which acts as a platform for antiviral signaling.
ENOSF1	Mitochondrial enolase superfamily member 1	Plays a role in the catabolism of L-fucose, a sugar that is part of the carbohydrates that are attached to cellular glycoproteins.
TIPIN	TIMELESS-interacting protein	Plays an important role in the control of DNA replication and the maintenance of replication fork stability.
ZFP42	Zinc finger protein 42 homolog	Involved in the reprogramming of X-chromosome inactivation during the acquisition of pluripotency.

Protein-family classification

Druggable: 21 · Difficult: 17 · Unknown: 37 · Druggable fraction: 0.28

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
Kinase	9	3.3×	0.013
Transcription factor	16	1.8×	0.073
Ion channel	1	1.5×	0.989
Enzyme (other)	7	1.1×	0.989
Other/Unknown	37	0.9×	0.989
Antibody/Immunoglobulin	2	0.8×	0.989
Protease	1	0.5×	0.989
GPCR	1	0.3×	0.989
Scaffold/PPI	1	0.2×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC28A1	Other/Unknown	no		CNT_N_dom, C_nuclsd_transpt, Gate_dom
SSR3	Other/Unknown	no		SSR3
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TEX14	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ankyrin_rpt
TFDP2	Transcription factor	no		E2F_WHTH_DNA-bd_dom, Transc_factor_DP_C, Transcrpt_fac_DP
TKTL1	Enzyme (other)	yes	2.2.1.1	Transketolase_N, Transketolase-like_Pyr-bd, Transketo_C/PFOR_II
TNFRSF17	Other/Unknown	no		BCMA_Tall-1-bd, TNFR_17, TNFR_13C/17
TYMS	Enzyme (other)	yes	2.1.1.45	Thymidylate_synthase, Thymidylate_synthase_AS, Thymidate_synth/dCMP_Mease_dom
UCK2	Kinase	yes	2.7.1.48	Uridine_kinase-like, PRK/URK, P-loop_NTPase
ZNF257	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
PRDM14	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_C2H2_sf
GAB2	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, Gab1-4-like
SPRY4	Other/Unknown	no		Sprouty, Sprouty_domain
MCM3AP-AS1	Other/Unknown	no
PKNOX2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
DLGAP5	Other/Unknown	no		SAPAP
CDKL2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
HPGDS	Enzyme (other)	yes	2.5.1.18	Glutathione_S-Trfase_N, GST_C, Glutathione-S-Trfase_C-like
ZNF638	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
TFCP2L1	Transcription factor	no		CP2, SAM/pointed_sf, TFCP2L1_SAM
SMARCAD1	Other/Unknown	no		SNF2_N, Helicase_C-like, CUE
CENPE	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
ZFPM1	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf
TBPL2	Other/Unknown	no		TBP, TBP_dom_sf, TBP_CS
ATG14	Enzyme (other)	yes	2.7.1.137	UV_resistance/autophagy_Atg14
USP35	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
ATF7IP	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, ATF7-int
FBXO34	Other/Unknown	no		F-box_dom, F-box-like_dom_sf, FBXO34/46
CLCN6	Other/Unknown	no		CBS_dom, ClC, Cl_channel-6
CATSPER3	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf
CLUL1	Other/Unknown	no		Clusterin-like, Clusterin_N, Clusterin_C
NCAPG2	Other/Unknown	no		ARM-like, ARM-type_fold, Condensin2_G2
BCAR4	Other/Unknown	no
NLRP12	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
GPR160	GPCR	yes		GPCR_Rhodpsn_7TM, GPR160
TIPARP	Transcription factor	no	2.4.2.30	Znf_CCCH, WWE_dom, Poly(ADP-ribose)pol_cat_dom
CLPTM1L	Other/Unknown	no		CLPTM1
RSL1D1	Other/Unknown	no		Ribosomal_uL1_3-a/b-sand, Ribosomal_uL1-like, Ribosomal_uL1/biogenesis
RFWD3	Transcription factor	no		WD40_rpt, Znf_RING, Znf_RING/FYVE/PHD
RESF1	Other/Unknown	no		RESF1
HEATR3	Other/Unknown	no		ARM-like, ARM-type_fold, SYO1-like
PLBD1	Enzyme (other)	yes	3.1.1.5	PLipase_B-like, ,
PRTG	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom
MPV17L	Other/Unknown	no		Mpv17_PMP22
DAZL	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
SLC25A44	Other/Unknown	no		MCP, MCP_transmembrane, MCP_dom_sf
DMRT1	Other/Unknown	no		DM_DNA-bd, DMRT1-like, DMRT

Expression context

Cohort genes with no expression data: 0.

65 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)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	13
oocyte	13
secondary oocyte	13
primordial germ cell in gonad	12
left testis	7
right testis	7
calcaneal tendon	6
ventricular zone	6
buccal mucosa cell	6
mucosa of transverse colon	4
monocyte	4
cortical plate	3
sural nerve	3
adrenal tissue	3
ileal mucosa	3
sperm	3
blood	3
leukocyte	3
right uterine tube	3
body of pancreas	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC28A1	90	tissue_specific	marker	right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis, liver
SSR3	279	ubiquitous	marker	body of pancreas, stromal cell of endometrium, calcaneal tendon
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TEX14	162	broad	marker	right testis, left testis, testis
TFDP2	276	ubiquitous	marker	calcaneal tendon, left testis, right testis
TKTL1	164	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
TNFRSF17	165	tissue_specific	marker	rectum, mucosa of transverse colon, jejunal mucosa
TYMS	262	ubiquitous	marker	ventricular zone, embryo, trabecular bone tissue
UCK2	238	ubiquitous	marker	mucosa of transverse colon, ventricular zone, ganglionic eminence
ZNF257	167	broad	marker	primordial germ cell in gonad, oocyte, male germ line stem cell (sensu Vertebrata) in testis
PRDM14	15	tissue_specific	marker	buccal mucosa cell, primordial germ cell in gonad, triceps brachii
GAB2	263	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, medulla oblongata
SPRY4	219	ubiquitous	marker	left coronary artery, right lung, ascending aorta
MCM3AP-AS1	206	ubiquitous	yes	buccal mucosa cell, cortical plate, male germ line stem cell (sensu Vertebrata) in testis
PKNOX2	236	broad	yes	pigmented layer of retina, sural nerve, right frontal lobe
DLGAP5	186	ubiquitous	marker	secondary oocyte, ventricular zone, oocyte
CDKL2	208	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
HPGDS	220	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, placenta, calcaneal tendon
ZNF638	300	ubiquitous	marker	calcaneal tendon, corpus callosum, cerebellar hemisphere
TFCP2L1	209	broad	marker	parotid gland, saliva-secreting gland, minor salivary gland
SMARCAD1	245	ubiquitous	marker	adrenal tissue, ganglionic eminence, tibia
CENPE	176	ubiquitous	marker	oocyte, ventricular zone, male germ line stem cell (sensu Vertebrata) in testis
ZFPM1	208	ubiquitous	marker	pancreatic ductal cell, ileal mucosa, nasal cavity epithelium
TBPL2	55		marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, sural nerve
ATG14	292	ubiquitous	marker	secondary oocyte, oocyte, gluteal muscle
USP35	183	ubiquitous	yes	secondary oocyte, oocyte, pancreatic ductal cell
ATF7IP	285	ubiquitous	marker	buccal mucosa cell, cardia of stomach, nipple
FBXO34	291	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, epithelium of esophagus

Protein interactions among cohort

Intra-cohort edges: 24.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIT	6,087
MAP2K1	5,944
TERT	5,717
STK11	5,146
GATA4	4,994
LGALS3	4,639
TYMS	4,628
FGFR3	4,510
RSL1D1	3,785
G3BP2	3,457

Intra-cohort edges

A	B	Sources
ATF7IP	CLPTM1L	string_interaction
ATF7IP	DMRT1	string_interaction
ATF7IP	SPRY4	string_interaction
ATF7IP	TERT	string_interaction
CENPE	MAD1L1	intact
CLPTM1L	DMRT1	string_interaction
CLPTM1L	TERT	string_interaction
CLUL1	ENOSF1	string_interaction
DAZL	PRDM14	string_interaction
DAZL	TEX14	string_interaction
DMRT1	KITLG	string_interaction
DMRT1	TEX14	string_interaction
ENOSF1	PDE8A	string_interaction
ENOSF1	TYMS	string_interaction
GAB2	ZNF638	biogrid_interaction
GATA4	ZFPM1	string_interaction
KATNA1	LATS1	biogrid_interaction
KIT	KITLG	biogrid_interaction, intact, string_interaction
MAD1L1	RFWD3	string_interaction
PRDM14	TFCP2L1	string_interaction
SLC28A1	TYMS	string_interaction
TFCP2L1	ZFP42	string_interaction
TYMS	UCK2	string_interaction
ZNF638	ZNF726	string_interaction

Structural data

PDB: 47 · AlphaFold-only: 26 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LGALS3	P17931	152
MAP2K1	Q02750	94
TYMS	P04818	61
BAK1	Q16611	55
KIT	P10721	52
HPGDS	O60760	30
TERT	O14746	23
RSL1D1	O76021	20
PIK3CD	O00329	18
FGFR3	P22607	15
TNFRSF17	Q02223	11
UCK2	Q9BZX2	11
GAB2	Q9UQC2	10
PDE8A	O60658	10
GSPT1	P15170	8
ATP1B3	P54709	8
ATG14	Q6ZNE5	7
AIFM3	Q96NN9	7
MCM3AP	O60318	7
CENPE	Q02224	6
KITLG	P21583	6
MAD1L1	Q9Y6D9	5
STK11	Q15831	4
DLGAP5	Q15398	4
SMARCAD1	Q9H4L7	4
USP35	Q9P2H5	4
LATS1	O95835	4
SSR3	Q9UNL2	3
HNF1B	P35680	3
CDKL2	Q92772	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TKTL1	P51854	94.74
PLBD1	Q6P4A8	92.07
MPV17L	Q2QL34	85.99
HEATR3	Q7Z4Q2	83.07
SLC28A1	O00337	81.94
SLC25A44	Q96H78	80.66
CATSPER3	Q86XQ3	80.01
TFCP2L1	Q9NZI6	79.32
CLPTM1L	Q96KA5	78.54
GPR160	Q9UJ42	76.87
PRTG	Q2VWP7	74.18
ZNF726	A6NNF4	74.01
TBPL2	Q6SJ96	70.12
TIPARP	Q7Z3E1	70.00
ZNF728	P0DKX0	69.18
ZNF257	Q9Y2Q1	67.58
CLUL1	Q15846	65.03
PITX1	P78337	62.81
PKNOX2	Q96KN3	61.38
PRDM14	Q9GZV8	60.83
DAZL	Q92904	57.38
ZFP42	Q96MM3	57.15
PIK3CD-AS1	Q5SR53	51.27
LINC00336	Q6ZUF6	50.36
FBXO34	Q9NWN3	49.31
RESF1	Q9HCM1	38.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 305. Enrichment computed across 76 evidence-associated genes (45 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 45 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Constitutive Signaling by Aberrant PI3K in Cancer	5	14.1×	0.008	GAB2, FGFR3, KIT, KITLG, PIK3CD
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	10.8×	0.014	GAB2, FGFR3, KIT, KITLG, PIK3CD
PIP3 activates AKT signaling	5	7.4×	0.054	GAB2, FGFR3, KIT, KITLG, PIK3CD
t(4;14) translocations of FGFR3	1	253.8×	0.057	FGFR3
Signaling by FGFR3 fusions in cancer	1	253.8×	0.057	FGFR3
Dasatinib-resistant KIT mutants	1	253.8×	0.057	KIT
Imatinib-resistant KIT mutants	1	253.8×	0.057	KIT
KIT mutants bind TKIs	1	253.8×	0.057	KIT
Masitinib-resistant KIT mutants	1	253.8×	0.057	KIT
Nilotinib-resistant KIT mutants	1	253.8×	0.057	KIT
Regorafenib-resistant KIT mutants	1	253.8×	0.057	KIT
Signaling by kinase domain mutants of KIT	1	253.8×	0.057	KIT
Sunitinib-resistant KIT mutants	1	253.8×	0.057	KIT
Signaling by juxtamembrane domain KIT mutants	1	253.8×	0.057	KIT
Sorafenib-resistant KIT mutants	1	253.8×	0.057	KIT
Drug resistance of KIT mutants	1	253.8×	0.057	KIT
Signaling by extracellular domain mutants of KIT	1	253.8×	0.057	KIT
Transcriptional regulation of testis differentiation	2	31.7×	0.057	DMRT1, GATA4
Regulation of KIT signaling	2	26.7×	0.057	KIT, KITLG
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	2	26.7×	0.057	HNF1B, GATA4
Signaling by SCF-KIT	3	16.6×	0.057	GAB2, KIT, KITLG
Interleukin receptor SHC signaling	2	18.1×	0.075	GAB2, PIK3CD
RAF/MAP kinase cascade	4	5.4×	0.081	FGFR3, KIT, KITLG, MAP2K1
G1/S-Specific Transcription	2	15.9×	0.089	TFDP2, TYMS
Signaling by CSF1 (M-CSF) in myeloid cells	2	15.4×	0.091	GAB2, PIK3CD
Activation and oligomerization of BAK protein	1	126.9×	0.092	BAK1
Developmental Lineage of Pancreatic Acinar Cells	2	13.4×	0.110	HNF1B, GATA4
Intrinsic Pathway for Apoptosis	2	13.0×	0.112	TFDP2, BAK1
Pyrophosphate hydrolysis	1	84.6×	0.120	LHPP
PI3K Cascade	2	12.1×	0.120	GAB2, FGFR3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 69 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inner cell mass cell fate commitment	2	162.8×	0.011	PRDM14, LATS1
melanocyte migration	2	162.8×	0.011	KIT, KITLG
embryonic hemopoiesis	3	43.1×	0.011	ZFPM1, KIT, KITLG
mast cell chemotaxis	2	122.1×	0.012	KIT, PIK3CD
mast cell differentiation	2	122.1×	0.012	KIT, PIK3CD
mitotic chromosome movement towards spindle pole	2	97.7×	0.012	DLGAP5, CENPE
positive regulation of mast cell cytokine production	2	97.7×	0.012	KIT, BCL10
mast cell proliferation	2	97.7×	0.012	KIT, KITLG
positive regulation of mast cell proliferation	2	97.7×	0.012	KIT, KITLG
primordial germ cell migration	2	54.3×	0.039	DMRT1, KIT
cell division	7	4.7×	0.043	TEX14, CENPE, NCAPG2, TIPIN, KATNA1, LATS1, MAD1L1
RNA-templated transcription	1	244.2×	0.051	TERT
T-helper cell lineage commitment	1	244.2×	0.051	ZFPM1
branched-chain amino acid transport	1	244.2×	0.051	SLC25A44
DNA strand elongation	1	244.2×	0.051	TERT
regulation of interleukin-18 production	1	244.2×	0.051	NLRP12
regulation of pronephros size	1	244.2×	0.051	HNF1B
pronephric nephron tubule development	1	244.2×	0.051	HNF1B
intercellular bridge organization	1	244.2×	0.051	TEX14
negative regulation of developmental growth	1	244.2×	0.051	FGFR3
negative regulation of mast cell differentiation	1	244.2×	0.051	ZFPM1
ureteric bud elongation	1	244.2×	0.051	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	244.2×	0.051	HNF1B
melanocyte adhesion	1	244.2×	0.051	KIT
microtubule plus-end directed mitotic chromosome migration	1	244.2×	0.051	CENPE
lateral attachment of mitotic spindle microtubules to kinetochore	1	244.2×	0.051	CENPE
positive regulation of pyloric antrum smooth muscle contraction	1	244.2×	0.051	KIT
siRNA transcription	1	244.2×	0.051	TERT
nucleoside import across plasma membrane	1	244.2×	0.051	SLC28A1
mesenchymal cell apoptotic process involved in metanephros development	1	244.2×	0.051	HNF1B

Therapeutics

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 15 · Phased (≥1): 17 · Undrugged: 58

Druggability breadth: 33 of 76 evidence-associated genes (43%) 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
SLC28A1	ADENOSINE
STK11	FEDRATINIB
TERT	BERBERINE
TYMS	FOLIC ACID
CDKL2	FEDRATINIB
TIPARP	OLAPARIB
FGFR3	PONATINIB
KIT	PONATINIB
LATS1	IBRUTINIB
MAP2K1	VEMURAFENIB
ATP1B3	OMEPRAZOLE
PDE8A	SILDENAFIL
PIK3CD	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIT	99	4
PIK3CD	66	4
FGFR3	64	4
MAP2K1	54	4
LATS1	32	4
CDKL2	21	4
STK11	17	4
TERT	10	4
TYMS	9	4
ATP1B3	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	SLC28A1
FEDRATINIB	4	CDKL2, FGFR3, KIT, MAP2K1, STK11
PACRITINIB	4	STK11
NINTEDANIB	4	CDKL2, FGFR3, KIT, LATS1, MAP2K1, STK11
SUNITINIB	4	CDKL2, FGFR3, KIT, LATS1, MAP2K1, PIK3CD
MIDOSTAURIN	4	FGFR3, KIT, LATS1, STK11
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
FOLIC ACID	4	TYMS
RALTITREXED	4	TYMS
PEMETREXED	4	TYMS
PEMETREXED DISODIUM	4	TYMS
METHOTREXATE	4	TYMS
PHENOLPHTHALEIN	4	TYMS
AXITINIB	4	CDKL2, FGFR3, KIT, MAP2K1
SORAFENIB	4	CDKL2, FGFR3, KIT, MAP2K1
QUIZARTINIB	4	CDKL2, KIT
CRIZOTINIB	4	CDKL2, FGFR3, KIT
OLAPARIB	4	TIPARP
PONATINIB	4	FGFR3, KIT
PEMIGATINIB	4	FGFR3
LENVATINIB	4	FGFR3, KIT
INFIGRATINIB PHOSPHATE	4	FGFR3, KIT
INFIGRATINIB	4	FGFR3, KIT
ENTRECTINIB	4	FGFR3, KIT
CERITINIB	4	FGFR3, KIT
VANDETANIB	4	FGFR3, KIT, MAP2K1
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3, KIT
ERDAFITINIB	4	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

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

Symbol	Assays	Type breakdown
KIT	2,305	Binding:2242, ADMET:32, Functional:22, Toxicity:9
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3
PIK3CD	1,111	Binding:1094, ADMET:8, Functional:8, Toxicity:1
FGFR3	975	Binding:948, Functional:18, ADMET:9
TERT	391	Binding:389, Functional:2
TYMS	376	Binding:373, ADMET:2, Functional:1
CENPE	346	Functional:241, Binding:105
GSPT1	267	Binding:266, Functional:1
STK11	244	Binding:244
LATS1	207	Binding:207
PDE8A	137	Binding:129, ADMET:6, Functional:2
LGALS3	127	Binding:127
CDKL2	108	Binding:108
HPGDS	90	Binding:89, ADMET:1
TIPARP	48	Binding:48
ATP1B3	47	Binding:47
BAK1	28	Binding:27, Functional:1
UCK2	25	Binding:25
KATNA1	19	Binding:19
SLC28A1	7	Binding:5, ADMET:2
GATA4	5	Binding:5
USP35	3	Binding:3
GPR160	3	Binding:3
TFDP2	2	Binding:2
RSL1D1	2	Binding:2
SSR3	1	Binding:1
PRDM14	1	Binding:1
ATG14	1	Binding:1
CLPTM1L	1	Binding:1
LHPP	1	Binding:1
G3BP2	1	Binding:1
KITLG	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase
TKTL1	2.2.1.1	transketolase
TYMS	2.1.1.45	thymidylate synthase
UCK2	2.7.1.48	uridine/cytidine kinase
HPGDS	2.5.1.18, 5.3.99.2	glutathione transferase, Prostaglandin-D synthase
ATG14	2.7.1.137	phosphatidylinositol 3-kinase
TIPARP	2.4.2.30	NAD+ ADP-ribosyltransferase
PLBD1	3.1.1.5	lysophospholipase
LHPP	3.9.1.3	phosphohistidine phosphatase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
KATNA1	5.6.1.1	microtubule-severing ATPase
KIT	2.7.10.1	receptor protein-tyrosine kinase
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase
PDE8A	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase
PIK3CD	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK11	244
TERT	391
TYMS	376
CDKL2	108
CENPE	346
FGFR3	975
GSPT1	267
KIT	2,305
LATS1	207
LGALS3	127
MAP2K1	1,200
PDE8A	137
PIK3CD	1,111

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

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

Compound	Max phase	Cohort target (bioactivity)
ADENOSINE	4	SLC28A1
FEDRATINIB	4	CDKL2, FGFR3, KIT, MAP2K1, STK11
PACRITINIB	4	STK11
NINTEDANIB	4	CDKL2, FGFR3, KIT, LATS1, MAP2K1, STK11
SUNITINIB	4	CDKL2, FGFR3, KIT, LATS1, MAP2K1, PIK3CD
MIDOSTAURIN	4	FGFR3, KIT, LATS1, STK11
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
FOLIC ACID	4	TYMS
RALTITREXED	4	TYMS
PEMETREXED	4	TYMS
PEMETREXED DISODIUM	4	TYMS
METHOTREXATE	4	TYMS
PHENOLPHTHALEIN	4	TYMS
AXITINIB	4	CDKL2, FGFR3, KIT, MAP2K1
SORAFENIB	4	CDKL2, FGFR3, KIT, MAP2K1
QUIZARTINIB	4	CDKL2, KIT
CRIZOTINIB	4	CDKL2, FGFR3, KIT
OLAPARIB	4	TIPARP
PONATINIB	4	FGFR3, KIT
PEMIGATINIB	4	FGFR3
LENVATINIB	4	FGFR3, KIT
INFIGRATINIB PHOSPHATE	4	FGFR3, KIT
INFIGRATINIB	4	FGFR3, KIT
ENTRECTINIB	4	FGFR3, KIT
CERITINIB	4	FGFR3, KIT
VANDETANIB	4	FGFR3, KIT, MAP2K1
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3, KIT
ERDAFITINIB	4	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	13	SLC28A1, STK11, TERT, TYMS, CDKL2, TIPARP, FGFR3, KIT, LATS1, MAP2K1 (+3 more)
B	Phased (≥1) drug, not yet approved	4	HPGDS, CENPE, LGALS3, BAK1
C	Druggable family + PDB, no drug	7	TEX14, UCK2, ATG14, USP35, ATF7IP, LHPP, KATNA1
D	Druggable family + AlphaFold only, no drug	5	TKTL1, CATSPER3, GPR160, PLBD1, PRTG
E	Difficult family or no structure, no drug	46	SSR3, HNF1B, TFDP2, TNFRSF17, ZNF257, PRDM14, GAB2, SPRY4, MCM3AP-AS1, PKNOX2 (+36 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLPTM1L	1	TERT
ENOSF1	0	TYMS
KITLG	1	KIT
GSPT1	267	—
SSR3	1	—
HNF1B	0	—
TEX14	0	—
TFDP2	2	—
TKTL1	0	—
TNFRSF17	0	—
UCK2	25	—
ZNF257	0	—
PRDM14	1	—
GAB2	0	—
SPRY4	0	—
MCM3AP-AS1	0	—
PKNOX2	0	—
DLGAP5	0	—
ZNF638	0	—
TFCP2L1	0	—
SMARCAD1	0	—
ZFPM1	0	—
TBPL2	0	—
ATG14	1	—
USP35	3	—
ATF7IP	0	—
FBXO34	0	—
CLCN6	0	—
CATSPER3	0	—
CLUL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 87.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	30
Not specified	25
PHASE3	13
PHASE1/PHASE2	9
PHASE1	9
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05417789	PHASE3	ACTIVE_NOT_RECRUITING	Study of Emactuzumab for Tenosynovial Giant Cell Tumor (TGCT)
NCT00002566	PHASE3	COMPLETED	Combination Chemotherapy With Bone Marrow Transplantation in Treating Men With Germ Cell Tumors
NCT00002596	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow or Stem Cell Transplantation in Treating Men With Untreated Germ Cell Tumors
NCT00003014	PHASE3	COMPLETED	Radiation Therapy Compared With Chemotherapy in Treating Patients With Stage I Testicular Cancer
NCT00003643	PHASE2/PHASE3	UNKNOWN	Combination Chemotherapy in Treating Men With Germ Cell Cancer
NCT00003941	PHASE3	COMPLETED	Combination Chemotherapy With or Without Peripheral Stem Cell Transplant in Treating Men With Previously Untreated Germ Cell Cancer
NCT00004219	PHASE3	UNKNOWN	Lerisetron Compared With Granisetron in Preventing Nausea and Vomiting in Men Being Treated With Radiation Therapy for Stage I Seminoma
NCT00005590	PHASE3	COMPLETED	Levofloxacin to Prevent Infection Following Chemotherapy in Treating Patients With Solid Tumors or Lymphoma
NCT00072215	PHASE3	TERMINATED	Cisplatin and Ifosfamide Combined With Either Paclitaxel or Vinblastine in Treating Men With Progressive or Recurrent Metastatic Germ Cell Tumors
NCT00104676	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT00324298	PHASE3	COMPLETED	Bleomycin, Etoposide, and Cisplatin in Treating Patients With Metastatic Germ Cell Cancer of the Testicles
NCT00324324	PHASE3	TERMINATED	Moxifloxacin in Preventing Bacterial Infections in Patients Who Have Undergone Donor Stem Cell Transplant
NCT00589537	PHASE3	UNKNOWN	Magnetic Resonance Imaging and Computed Tomography in Patients With Stage I Seminoma of the Testicle
NCT01087268	PHASE3	UNKNOWN	Hyperbaric Oxygen Therapy in Treating Long-Term Gastrointestinal Adverse Effects Caused by Radiation Therapy in Patients With Pelvic Cancer
NCT06041503	PHASE2	RECRUITING	Enfortumab Vedotin With or Without Pembrolizumab in Rare Genitourinary Tumors (E-VIRTUE)
NCT00002508	PHASE1/PHASE2	COMPLETED	Combination Chemotherapy Followed by Bone Marrow or Stem Cell Transplantation in Treating Patients With Relapsed or Refractory Germ Cell Tumors
NCT00002515	PHASE2	COMPLETED	Combination Chemotherapy Followed by Bone Marrow Transplantation in Treating Patients With Rare Cancer
NCT00002558	PHASE1/PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Germ Cell Tumors
NCT00002559	PHASE1/PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Germ Cell Tumors That Have Not Responded to Previous Cisplatin
NCT00002903	PHASE2	COMPLETED	Docetaxel in Treating Patients With Recurrent or Refractory Germ Cell Cancer
NCT00002931	PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00002943	PHASE2	COMPLETED	Carboplatin, Etoposide, Cyclophosphamide, and Autologous Bone Marrow Transplantation in Patients With Relapsed or Refractory Cancer
NCT00003173	PHASE2	COMPLETED	High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors
NCT00003408	PHASE2	COMPLETED	Biological Therapy Following Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Cancer
NCT00003518	PHASE2	COMPLETED	Paclitaxel Plus Gemcitabine in Treating Patients With Refractory Metastatic Germ Cell Tumors
NCT00003657	PHASE2	COMPLETED	High-dose ICE With Amifostine
NCT00003852	PHASE2	TERMINATED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Germ Cell Tumors
NCT00003887	PHASE2	COMPLETED	Lymphocyte Infusion in Treating Patients With Relapsed Cancer After Bone Marrow or Peripheral Stem Cell Transplantation
NCT00004077	PHASE2	COMPLETED	Paclitaxel, Ifosfamide, and Cisplatin in Treating Patients With Metastatic Testicular Cancer
NCT00004157	PHASE2	COMPLETED	Interleukin-11 Plus Filgrastim Prior to Peripheral Stem Cell Transplantation in Patients With Non-Hodgkin’s Lymphoma, Hodgkin’s Disease, Breast Cancer, or Other Solid Tumors
NCT00005952	PHASE1/PHASE2	COMPLETED	Temozolomide Plus Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Malignant Glioma or Recurrent CNS or Other Solid Tumors
NCT00006043	PHASE2	COMPLETED	Temozolomide in Treating Patients With Metastatic Germ Cell Tumors That Have Not Responded to Cisplatin
NCT00010283	PHASE1/PHASE2	COMPLETED	Beclomethasone in Treating Patients With Graft-Versus-Host Disease of the Esophagus, Stomach, Small Intestine, or Colon
NCT00019331	PHASE2	COMPLETED	Vaccine Therapy Plus Biological Therapy in Treating Adults With Metastatic Solid Tumors
NCT00036842	PHASE2	COMPLETED	Arsenic Trioxide in Treating Men With Germ Cell Cancer
NCT00060255	PHASE2	COMPLETED	High-Dose Chemotherapy, Total-Body Irradiation, and Autologous Stem Cell Transplantation or Bone Marrow Transplantation in Treating Patients With Hematologic Cancer or Solid Tumors
NCT00064311	PHASE1/PHASE2	COMPLETED	Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation
NCT00070096	PHASE2	COMPLETED	Ixabepilone in Treating Patients With Advanced Cisplatin-Refractory Germ Cell Tumors
NCT00109993	PHASE2	COMPLETED	Campath-1H + FK506 and Methylprednisolone for GVHD
NCT00301782	PHASE2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IFOSFAMIDE	4	15
BLEOMYCIN SULFATE	4	7
CYCLOPHOSPHAMIDE ANHYDROUS	4	6
GRANISETRON	4	6
CISPLATIN	4	4
ETOPOSIDE	4	4
THIOTEPA	4	4
CARBOPLATIN	4	3
FILGRASTIM	4	3
VINBLASTINE	4	3
ALEMTUZUMAB	4	2
DASATINIB ANHYDROUS	4	2
ETOPOSIDE PHOSPHATE	4	2
LEVOFLOXACIN ANHYDROUS	4	2
METHYLPREDNISOLONE	4	2
SARGRAMOSTIM	4	2
ALDESLEUKIN	4	1
AMIFOSTINE	4	1
ARSENIC TRIOXIDE	4	1
BECLOMETHASONE DIPROPIONATE	4	1
CARMUSTINE	4	1
ENFORTUMAB VEDOTIN	4	1
EPIRUBICIN HYDROCHLORIDE	4	1
IXABEPILONE	4	1
LENOGRASTIM	4	1
MOXIFLOXACIN HYDROCHLORIDE	4	1
OFLOXACIN	4	1
OXALIPLATIN	4	1
PACLITAXEL	4	1
PALBOCICLIB	4	1