Primary amenorrhea

Summary

Primary amenorrhea (MONDO:1060208) is a disease with 53 cohort genes and 1 clinical trial. The dominant Reactome pathway is Post-translational protein modification (7 cohort genes).

At a glance

• Cohort genes: 53
• ClinVar variants: 91
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	primary amenorrhea
Mondo ID	MONDO:1060208
UMLS	C0232939
MedGen	115918
Is cancer (heuristic)	no

Data availability: 91 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › female reproductive system disorder › menstrual disorder › amenorrhea › primary amenorrhea

Related subtypes (2): calloso-genital dysplasia, secondary amenorrhea

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

91 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 35 likely benign, 13 benign, 3 likely pathogenic, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
549656	NC_000023.10:g.50653777_50689335del35559	BMP15	Pathogenic	criteria provided, single submitter
996695	NM_003680.4(YARS1):c.806T>C (p.Phe269Ser)	LOC126805688	Pathogenic/Likely pathogenic	no assertion criteria provided
549640	NC_000015.9:g.83214012_84812693del1598682	ADAMTSL3	Likely pathogenic	criteria provided, single submitter
549627	NC_000010.10:g.135252327_135378761del126435	CYP2E1	Likely pathogenic	criteria provided, single submitter
549659	NC_000023.11:g.97519547_97572671dup	DIAPH2	Likely pathogenic	criteria provided, single submitter
267801	46;X;t(X;8;2)(Xpter>Xq21.2::2q14.2>2qter;8qter>8p11.1::Xq21.2>Xqter;2pter>2q14.2::8p11.1>8pter)dn		Uncertain significance	criteria provided, single submitter
267964	46;XX;add(1)(q32.1)		Uncertain significance	criteria provided, single submitter
549584	NC_000002.12:g.35742924_35765778dup		Uncertain significance	criteria provided, single submitter
549623	NC_000009.11:g.24242825_24310533del67709		Uncertain significance	criteria provided, single submitter
549644	NC_000018.10:g.62431580_62441327del		Uncertain significance	criteria provided, single submitter
549652	Single allele	AMELX	Uncertain significance	criteria provided, single submitter
549643	NC_000016.10:g.56402918_56428075dup	AMFR	Uncertain significance	criteria provided, single submitter
549647	Single allele	ANKRD24	Uncertain significance	criteria provided, single submitter
549595	NC_000005.9:g.112179040_112192379del13340	APC	Uncertain significance	criteria provided, single submitter
549597	NC_000005.10:g.160592205_161364688dup	ATP10B	Uncertain significance	criteria provided, single submitter
549639	NC_000015.9:g.34125784_34151995del26212	AVEN	Uncertain significance	criteria provided, single submitter
549638	NC_000014.8:g.54195768_54215968del20201	BMP4	Uncertain significance	criteria provided, single submitter
549641	NM_001365242.1(CPEB1):c.-98+1610_-98+5362del	CPEB1	Uncertain significance	criteria provided, single submitter
549628	NC_000010.11:g.133438823_133565257dup	CYP2E1	Uncertain significance	criteria provided, single submitter
549629	NC_000010.11:g.133468178_133564028dup	CYP2E1	Uncertain significance	criteria provided, single submitter
549630	NC_000010.11:g.133468178_133565257dup	CYP2E1	Uncertain significance	criteria provided, single submitter
549631	NC_000010.11:g.133468178_133591019dup	CYP2E1	Uncertain significance	criteria provided, single submitter
549581	Single allele	DDX1	Uncertain significance	criteria provided, single submitter
549590	NC_000003.12:g.57686154_57804308dup	DENND6A	Uncertain significance	criteria provided, single submitter
549604	NC_000006.12:g.170299941_170556913dup	FAM120B	Uncertain significance	criteria provided, single submitter
549616	NC_000008.10:g.104306192_104334440del28249	FZD6	Uncertain significance	criteria provided, single submitter
549586	NC_000003.12:g.127814446_127916946dup	KBTBD12	Uncertain significance	criteria provided, single submitter
549596	NC_000005.9:g.152263564_152321761del58198	LINC01470	Uncertain significance	criteria provided, single submitter
549648	NC_000020.10:g.51258881_51372398del113518	LINC01524	Uncertain significance	criteria provided, single submitter
549632	NC_000010.11:g.33846064_33943640dup	LINC02629	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP15	Orphanet:243	46,XX gonadal dysgenesis
BMP15	Orphanet:398987	Malignant teratoma of ovary
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
VLDLR	Orphanet:1766	Dysequilibrium syndrome
XPO1	Orphanet:98838	Primary mediastinal large B-cell lymphoma
CDK13	Orphanet:646278	CDK13-related developmental delay-intellectual disability-facial dysmorphism-congenital heart defects syndrome
FHIT	Orphanet:422526	Hereditary clear cell renal cell carcinoma
FZD6	Orphanet:280654	Autosomal recessive nail dysplasia
AMELX	Orphanet:100033	Hypomaturation amelogenesis imperfecta
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor
ARSA	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
ARSA	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
ARSA	Orphanet:309271	Metachromatic leukodystrophy, adult form

Cohort genes → proteins

53 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	53

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMP15	HGNC:1068	ENSG00000130385	O95972	Bone morphogenetic protein 15	clinvar
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	clinvar
VLDLR	HGNC:12698	ENSG00000147852	P98155	Very low-density lipoprotein receptor	clinvar
XPO1	HGNC:12825	ENSG00000082898	O14980	Exportin-1	clinvar
TSHZ2	HGNC:13010	ENSG00000182463	Q9NRE2	Teashirt homolog 2	clinvar
AVEN	HGNC:13509	ENSG00000169857	Q9NQS1	Cell death regulator Aven	clinvar
ATP10B	HGNC:13543	ENSG00000118322	O94823	Phospholipid-transporting ATPase VB	clinvar
ADAMTSL3	HGNC:14633	ENSG00000156218	P82987	ADAMTS-like protein 3	clinvar
GPR37L1	HGNC:14923	ENSG00000170075	O60883	G-protein coupled receptor 37-like 1	clinvar
DUSP22	HGNC:16077	ENSG00000112679	Q9NRW4	Dual specificity protein phosphatase 22	clinvar
CD1E	HGNC:1638	ENSG00000158488	P15812	T-cell surface glycoprotein CD1e, membrane-associated	clinvar
CDK13	HGNC:1733	ENSG00000065883	Q14004	Cyclin-dependent kinase 13	clinvar
ABHD2	HGNC:18717	ENSG00000140526	P08910	Monoacylglycerol lipase ABHD2	clinvar
DUSP19	HGNC:18894	ENSG00000162999	Q8WTR2	Dual specificity protein phosphatase 19	clinvar
OR51B5	HGNC:19599	ENSG00000167355	Q9H339	Olfactory receptor 51B5	clinvar
FAM120B	HGNC:21109	ENSG00000112584	Q96EK7	Constitutive coactivator of peroxisome proliferator-activated receptor gamma	clinvar
CPEB1	HGNC:21744	ENSG00000214575	Q9BZB8	Cytoplasmic polyadenylation element-binding protein 1	clinvar
ADARB2	HGNC:227	ENSG00000185736	Q9NS39	Inactive double-stranded RNA-specific editase B2	clinvar
CNTLN	HGNC:23432	ENSG00000044459	Q9NXG0	Centlein	clinvar
ERI1	HGNC:23994	ENSG00000104626	Q8IV48	3’-5’ exoribonuclease 1	clinvar
BCAP29	HGNC:24131	ENSG00000075790	Q9UHQ4	B-cell receptor-associated protein 29	clinvar
AHCTF1	HGNC:24618	ENSG00000153207	Q8WYP5	Protein ELYS	clinvar
PNPLA4	HGNC:24887	ENSG00000006757	P41247	Patatin-like phospholipase domain-containing protein 4	clinvar
CCDC148	HGNC:25191	ENSG00000153237	Q8NFR7	Coiled-coil domain-containing protein 148	clinvar
KBTBD12	HGNC:25731	ENSG00000187715	Q3ZCT8	Kelch repeat and BTB domain-containing protein 12	clinvar
CYP2E1	HGNC:2631	ENSG00000130649	P05181	Cytochrome P450 2E1	clinvar
DENND6A	HGNC:26635	ENSG00000174839	Q8IWF6	Protein DENND6A	clinvar
DDX1	HGNC:2734	ENSG00000079785	Q92499	ATP-dependent RNA helicase DDX1	clinvar
GXYLT1	HGNC:27482	ENSG00000151233	Q4G148	Glucoside xylosyltransferase 1	clinvar
GADL1	HGNC:27949	ENSG00000144644	Q6ZQY3	Acidic amino acid decarboxylase GADL1	clinvar
DIAPH2	HGNC:2877	ENSG00000147202	O60879	Protein diaphanous homolog 2	clinvar
GPBP1L1	HGNC:28843	ENSG00000159592	Q9HC44	Vasculin-like protein 1	clinvar
DLC1	HGNC:2897	ENSG00000164741	Q96QB1	Rho GTPase-activating protein 7	clinvar
CCSER1	HGNC:29349	ENSG00000184305	Q9C0I3	Serine-rich coiled-coil domain-containing protein 1	clinvar
ANKRD24	HGNC:29424	ENSG00000089847	Q8TF21	Ankyrin repeat domain-containing protein 24	clinvar
NCKAP5	HGNC:29847	ENSG00000176771	O14513	Nck-associated protein 5	clinvar
FHIT	HGNC:3701	ENSG00000189283	P49789	Bis(5’-adenosyl)-triphosphatase	clinvar
FZD6	HGNC:4044	ENSG00000164930	O60353	Frizzled-6	clinvar
MIR4500HG	HGNC:42773	ENSG00000228824		MIR4500 host gene	clinvar
AMELX	HGNC:461	ENSG00000125363	Q99217	Amelogenin, X isoform	clinvar
AMFR	HGNC:463	ENSG00000159461	Q9UKV5	E3 ubiquitin-protein ligase AMFR	clinvar
GTF2H2	HGNC:4656	ENSG00000145736	Q13888	General transcription factor IIH subunit 2	clinvar
LINC00879	HGNC:48566	ENSG00000239589		long intergenic non-protein coding RNA 879	clinvar
LINC01470	HGNC:51105	ENSG00000249484		long intergenic non-protein coding RNA 1470	clinvar
LINC01524	HGNC:51228	ENSG00000234948		long intergenic non-protein coding RNA 1524	clinvar
LINC02629	HGNC:54108	ENSG00000223470		long intergenic non-protein coding RNA 2629	clinvar
LINC02714	HGNC:54231	ENSG00000251226		long intergenic non-protein coding RNA 2714	clinvar
MAGEA3-DT	HGNC:56247	ENSG00000287394		MAGEA3 divergent transcript	clinvar
LINC03077	HGNC:56657	ENSG00000281566		long intergenic non-protein coding RNA 3077	clinvar
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP15	Bone morphogenetic protein 15	May be involved in follicular development.
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.
VLDLR	Very low-density lipoprotein receptor	Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism.
XPO1	Exportin-1	Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs.
TSHZ2	Teashirt homolog 2	Probable transcriptional regulator involved in developmental processes.
AVEN	Cell death regulator Aven	Protects against apoptosis mediated by Apaf-1.
ATP10B	Phospholipid-transporting ATPase VB	Catalytic component of a P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of glucosylceramide (GlcCer) from the outer to the inner leaflet of lysosome membranes.
GPR37L1	G-protein coupled receptor 37-like 1	G-protein coupled receptor.
DUSP22	Dual specificity protein phosphatase 22	Dual specificity phosphatase; can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues.
CD1E	T-cell surface glycoprotein CD1e, membrane-associated	T-cell surface glycoprotein CD1e, soluble binds diacetylated lipids, including phosphatidyl inositides and diacylated sulfoglycolipids, and is required for the presentation of glycolipid antigens on the cell surface.
CDK13	Cyclin-dependent kinase 13	Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing.
ABHD2	Monoacylglycerol lipase ABHD2	Progesterone-dependent acylglycerol lipase that catalyzes hydrolysis of endocannabinoid arachidonoylglycerol (AG) from cell membrane.
DUSP19	Dual specificity protein phosphatase 19	Has a dual specificity toward Ser/Thr and Tyr-containing proteins.
OR51B5	Olfactory receptor 51B5	Odorant receptor.
FAM120B	Constitutive coactivator of peroxisome proliferator-activated receptor gamma	Functions as a transactivator of PPARG and ESR1.
CPEB1	Cytoplasmic polyadenylation element-binding protein 1	Sequence-specific RNA-binding protein that regulates mRNA cytoplasmic polyadenylation and translation initiation during oocyte maturation, early development and at postsynapse sites of neurons.
ADARB2	Inactive double-stranded RNA-specific editase B2	Single- and double-stranded RNA-binding protein that interferes with the RNA editing activities of ADAR/ADAR1 and ADARB1/ADAR2.
CNTLN	Centlein	Required for centrosome cohesion and recruitment of CEP68 to centrosomes.
ERI1	3’-5’ exoribonuclease 1	RNA exonuclease that binds to the 3’-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication.
BCAP29	B-cell receptor-associated protein 29	May play a role in anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi.
AHCTF1	Protein ELYS	Required for the assembly of a functional nuclear pore complex (NPC) on the surface of chromosomes as nuclei form at the end of mitosis.
PNPLA4	Patatin-like phospholipase domain-containing protein 4	Has abundant triacylglycerol lipase activity.
CYP2E1	Cytochrome P450 2E1	A cytochrome P450 monooxygenase involved in the metabolism of fatty acids.
DENND6A	Protein DENND6A	Guanine nucleotide exchange factor (GEF) for RAB14.
DDX1	ATP-dependent RNA helicase DDX1	Acts as an ATP-dependent RNA helicase, able to unwind both RNA-RNA and RNA-DNA duplexes.
GXYLT1	Glucoside xylosyltransferase 1	Glycosyltransferase which elongates the O-linked glucose attached to EGF-like repeats in the extracellular domain of Notch proteins by catalyzing the addition of xylose.
GADL1	Acidic amino acid decarboxylase GADL1	May catalyze the decarboxylation of L-aspartate, 3-sulfino-L-alanine (cysteine sulfinic acid), and L-cysteate to beta-alanine, hypotaurine and taurine, respectively.
DIAPH2	Protein diaphanous homolog 2	Could be involved in oogenesis.
GPBP1L1	Vasculin-like protein 1	Possible transcription factor.
DLC1	Rho GTPase-activating protein 7	Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling.
ANKRD24	Ankyrin repeat domain-containing protein 24	Component of the stereocilia rootlet in hair cells of inner ear.
FHIT	Bis(5’-adenosyl)-triphosphatase	Possesses dinucleoside triphosphate hydrolase activity.
FZD6	Frizzled-6	Receptor for Wnt proteins.
AMELX	Amelogenin, X isoform	Plays a role in biomineralization.
AMFR	E3 ubiquitin-protein ligase AMFR	E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation.
GTF2H2	General transcription factor IIH subunit 2	Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription…
APC	Adenomatous polyposis coli protein	Tumor suppressor.
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.
ASMTL	Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein	Nucleoside triphosphate pyrophosphatase that hydrolyzes dTTP and UTP.
NCAM2	Neural cell adhesion molecule 2	May play important roles in selective fasciculation and zone-to-zone projection of the primary olfactory axons.

Protein-family classification

Druggable: 11 · Difficult: 5 · Unknown: 37 · Druggable fraction: 0.21

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
Phosphatase	3	4.8×	0.105
Other/Unknown	37	1.2×	0.105
Antibody/Immunoglobulin	3	1.6×	0.727
GPCR	3	1.4×	0.765
Transcription factor	4	0.6×	0.990
Kinase	1	0.5×	0.990
Scaffold/PPI	1	0.3×	0.990
Enzyme (other)	1	0.2×	0.990

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP15	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
VLDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
XPO1	Other/Unknown	no		Importin-beta_N, ARM-like, Exportin-1/Importin-b-like
TSHZ2	Transcription factor	no		HD, Znf_C2H2_type, Teashirt_fam
AVEN	Other/Unknown	no		Aven
ATP10B	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
ADAMTSL3	Antibody/Immunoglobulin	yes		TSP1_rpt, Ig_sub2, Ig_sub
GPR37L1	GPCR	yes		GPCR_Rhodpsn, GPR37_orph, GPCR_Rhodpsn_7TM
DUSP22	Phosphatase	yes		Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, TYR_PHOSPHATASE_DUAL_dom
CD1E	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig-like_dom, MHC_I-like_Ag-recog
CDK13	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ABHD2	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_4_CS, ABHD4
DUSP19	Phosphatase	yes		Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, TYR_PHOSPHATASE_DUAL_dom
OR51B5	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
FAM120B	Other/Unknown	no		Coact_PPARg, PIN-like_dom_sf
CPEB1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, CEBP1_N
ADARB2	Other/Unknown	no		A_deamin, dsRBD_dom, ADAR3_DSRM_1
CNTLN	Other/Unknown	no		CNTLN
ERI1	Other/Unknown	no		SAP_dom, RNaseH-like_sf, Ribonucl_H
BCAP29	Other/Unknown	no		BAP29/BAP31, BAP29/BAP31_N, Bap31/Bap29_C
AHCTF1	Other/Unknown	no		Quinoprotein_ADH-like_sf, ELYS_dom, ELYS-bb
PNPLA4	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
CCDC148	Other/Unknown	no		CCDC148/CCDC112
KBTBD12	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
CYP2E1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2E-like
DENND6A	Other/Unknown	no		ABL9/DENND6_dom, DENND6, Tripartite_DENN
DDX1	Other/Unknown	no		Helicase_C-like, B30.2/SPRY, SPRY_dom
GXYLT1	Other/Unknown	no		Glyco_trans_8, Nucleotide-diphossugar_trans, Glycosyltransferase_8
GADL1	Other/Unknown	no		PyrdxlP-dep_de-COase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
DIAPH2	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
GPBP1L1	Other/Unknown	no		Vasculin_fam
DLC1	Other/Unknown	no		RhoGAP_dom, SAM, START_lipid-bd_dom
CCSER1	Other/Unknown	no		CCSER
ANKRD24	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, RAI14/UACA
NCKAP5	Other/Unknown	no		Nckap5l, NCKAP5_C
FHIT	Enzyme (other)	yes	3.6.1.29	HIT-like, Histidine_triad_CS, HIT-like_sf
FZD6	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
MIR4500HG	Other/Unknown	no
AMELX	Other/Unknown	no		Amelogenin
AMFR	Transcription factor	no	2.3.2.27	Znf_RING, CUE, Znf_RING/FYVE/PHD
GTF2H2	Transcription factor	no		VWF_A, TFIIH_C1-like_dom, Ssl1-like
LINC00879	Other/Unknown	no
LINC01470	Other/Unknown	no
LINC01524	Other/Unknown	no
LINC02629	Other/Unknown	no
LINC02714	Other/Unknown	no
MAGEA3-DT	Other/Unknown	no
LINC03077	Other/Unknown	no
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP

Expression context

Cohort genes with no expression data: 0.

44 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)	52
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	12
buccal mucosa cell	8
secondary oocyte	7
primordial germ cell in gonad	6
calcaneal tendon	5
sural nerve	5
oocyte	4
ventricular zone	4
right testis	4
adrenal tissue	4
heart right ventricle	3
germinal epithelium of ovary	3
palpebral conjunctiva	3
bronchial epithelial cell	3
parietal pleura	3
monocyte	3
pigmented layer of retina	2
rectum	2
caput epididymis	2
corpus epididymis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP15	8		yes	secondary oocyte, oocyte, pancreatic ductal cell
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
VLDLR	273	ubiquitous	marker	heart right ventricle, left ovary, right ovary
XPO1	294	ubiquitous	marker	tibia, ventricular zone, germinal epithelium of ovary
TSHZ2	230	broad	marker	buccal mucosa cell, corpus epididymis, caput epididymis
AVEN	252	ubiquitous	marker	heart right ventricle, cervix squamous epithelium, ascending aorta
ATP10B	220	tissue_specific	marker	mucosa of sigmoid colon, colonic mucosa, palpebral conjunctiva
ADAMTSL3	218	broad	marker	calcaneal tendon, descending thoracic aorta, thoracic aorta
GPR37L1	146	broad	marker	buccal mucosa cell, caudate nucleus, medial globus pallidus
DUSP22	286	ubiquitous	marker	secondary oocyte, cervix squamous epithelium, gingival epithelium
CD1E	148	tissue_specific	marker	thymus, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
CDK13	297	ubiquitous	marker	buccal mucosa cell, renal medulla, visceral pleura
ABHD2	278	ubiquitous	marker	corpus epididymis, calcaneal tendon, islet of Langerhans
DUSP19	178	ubiquitous	yes	oocyte, secondary oocyte, buccal mucosa cell
OR51B5	112	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte
FAM120B	134	ubiquitous	marker	right uterine tube, right testis, left testis
CPEB1	132	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, C1 segment of cervical spinal cord, pituitary gland
ADARB2	184	broad	marker	C1 segment of cervical spinal cord, spinal cord, substantia nigra
CNTLN	195	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, ventricular zone
ERI1	211	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, oocyte
BCAP29	167	ubiquitous	marker	calcaneal tendon, smooth muscle tissue, right lobe of thyroid gland
AHCTF1	283	ubiquitous	marker	endothelial cell, calcaneal tendon, secondary oocyte
PNPLA4	276	ubiquitous	marker	oocyte, hindlimb stylopod muscle, diaphragm
CCDC148	172		marker	bronchial epithelial cell, bronchus, male germ line stem cell (sensu Vertebrata) in testis
KBTBD12	180	tissue_specific	marker	tibialis anterior, quadriceps femoris, vastus lateralis
CYP2E1	231	tissue_specific	marker	right lobe of liver, liver, lower esophagus mucosa
DENND6A	259	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, palpebral conjunctiva
DDX1	301	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, heart right ventricle
GXYLT1	236	ubiquitous	yes	pigmented layer of retina, parietal pleura, adrenal tissue
GADL1	79	tissue_specific	marker	buccal mucosa cell, germinal epithelium of ovary, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XPO1	7,582
DDX1	5,253
BMP4	4,425
APC	2,903
CYP2E1	2,705
CDK13	2,621
ASMTL	2,493
GADL1	1,889
VLDLR	1,817
DUSP22	1,813

Intra-cohort edges

A	B	Sources
APC	NCKAP5	biogrid_interaction, intact
BMP15	DIAPH2	string_interaction
CCSER1	FHIT	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 23 · No structure: 8

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GTF2H2	Q13888	52
APC	P25054	31
VLDLR	P98155	27
XPO1	O14980	18
AMFR	Q9UKV5	13
ARSA	P15289	10
FHIT	P49789	9
NCAM2	O15394	9
DUSP22	Q9NRW4	8
DLC1	Q96QB1	7
CYP2E1	P05181	6
CPEB1	Q9BZB8	5
ERI1	Q8IV48	5
DUSP19	Q8WTR2	4
BCAP29	Q9UHQ4	3
ASMTL	O95671	3
CDK13	Q14004	2
AHCTF1	Q8WYP5	2
DDX1	Q92499	2
FZD6	O60353	2
CD1E	P15812	1
KBTBD12	Q3ZCT8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GADL1	Q6ZQY3	94.77
PNPLA4	P41247	94.38
ABHD2	P08910	91.06
OR51B5	Q9H339	89.75
GXYLT1	Q4G148	85.06
DENND6A	Q8IWF6	84.94
CCDC148	Q8NFR7	79.14
BMP4	P12644	79.12
DIAPH2	O60879	76.09
BMP15	O95972	72.64
FAM120B	Q96EK7	71.92
ADARB2	Q9NS39	71.69
ATP10B	O94823	71.60
CNTLN	Q9NXG0	71.14
ANKRD24	Q8TF21	70.30
GPR37L1	O60883	67.95
ADAMTSL3	P82987	65.99
AMELX	Q99217	59.51
AVEN	Q9NQS1	58.86
GPBP1L1	Q9HC44	55.20
TSHZ2	Q9NRE2	54.88
CCSER1	Q9C0I3	47.56
NCKAP5	O14513	43.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 175. Enrichment computed across 53 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Post-translational protein modification	7	5.2×	0.049	BMP15, BMP4, ADAMTSL3, AMELX, AMFR, APC, ARSA
APC truncation mutants are not K63 polyubiquitinated	1	439.2×	0.128	APC
Post-translational protein phosphorylation	3	11.6×	0.128	BMP15, BMP4, AMELX
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	3	10.0×	0.128	BMP15, BMP4, AMELX
RHO GTPases Activate Formins	3	9.0×	0.128	XPO1, AHCTF1, DIAPH2
Metabolism of proteins	7	3.3×	0.128	BMP15, BMP4, ADAMTSL3, AMELX, AMFR, APC, ARSA
Deactivation of the beta-catenin transactivating complex	2	17.9×	0.137	XPO1, APC
Formation of lateral plate mesoderm	1	87.8×	0.140	BMP4
Reelin signalling pathway	1	73.2×	0.140	VLDLR
VLDL clearance	1	73.2×	0.140	VLDLR
Biosynthesis of maresin-like SPMs	1	73.2×	0.140	CYP2E1
Formation of apoptosome	1	54.9×	0.140	AVEN
Formation of intermediate mesoderm	1	54.9×	0.140	BMP4
Cytochrome c-mediated apoptotic response	1	48.8×	0.140	AVEN
HuR (ELAVL1) binds and stabilizes mRNA	1	48.8×	0.140	XPO1
Signaling by RNF43 mutants	1	48.8×	0.140	FZD6
Signaling by AXIN mutants	1	39.9×	0.140	APC
Signaling by CTNNB1 phospho-site mutants	1	39.9×	0.140	APC
Signaling by APC mutants	1	39.9×	0.140	APC
Signaling by AMER1 mutants	1	39.9×	0.140	APC
Aspartate and asparagine metabolism	1	39.9×	0.140	GADL1
Regulation of the apoptosome activity	1	39.9×	0.140	AVEN
Degradation of cysteine and homocysteine	1	36.6×	0.140	GADL1
CYP2E1 reactions	1	36.6×	0.140	CYP2E1
Apoptotic factor-mediated response	1	33.8×	0.140	AVEN
The activation of arylsulfatases	1	33.8×	0.140	ARSA
Specification of primordial germ cells	1	33.8×	0.140	BMP4
APC truncation mutants have impaired AXIN binding	1	31.4×	0.140	APC
AXIN missense mutants destabilize the destruction complex	1	31.4×	0.140	APC
Truncations of AMER1 destabilize the destruction complex	1	31.4×	0.140	APC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 43 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
diadenosine triphosphate catabolic process	1	391.9×	0.046	FHIT
carbon tetrachloride metabolic process	1	391.9×	0.046	CYP2E1
benzene metabolic process	1	391.9×	0.046	CYP2E1
4-nitrophenol metabolic process	1	391.9×	0.046	CYP2E1
halogenated hydrocarbon metabolic process	1	391.9×	0.046	CYP2E1
intermediate mesodermal cell differentiation	1	391.9×	0.046	BMP4
positive regulation of cardiac muscle fiber development	1	391.9×	0.046	BMP4
bronchus development	1	391.9×	0.046	BMP4
bud dilation involved in lung branching	1	391.9×	0.046	BMP4
mammary gland formation	1	391.9×	0.046	BMP4
negative regulation of mesenchymal cell proliferation involved in ureter development	1	391.9×	0.046	BMP4
negative regulation of glomerulus development	1	391.9×	0.046	BMP4
lysosomal membrane organization	1	391.9×	0.046	ATP10B
regulation of mesodermal cell differentiation	1	391.9×	0.046	BMP4
negative regulation of metanephric S-shaped body morphogenesis	1	391.9×	0.046	BMP4
negative regulation of metanephric comma-shaped body morphogenesis	1	391.9×	0.046	BMP4
female gamete generation	2	37.3×	0.046	BMP15, DIAPH2
negative regulation of focal adhesion assembly	2	35.6×	0.046	DUSP22, DLC1
positive regulation of collagen biosynthetic process	2	30.1×	0.046	BMP4, AMELX
neural tube closure	3	13.1×	0.046	BMP4, DLC1, FZD6
tendon cell differentiation	1	195.9×	0.059	BMP4
positive regulation of branching involved in lung morphogenesis	1	195.9×	0.059	BMP4
negative regulation of glomerular mesangial cell proliferation	1	195.9×	0.059	BMP4
negative regulation of branching involved in ureteric bud morphogenesis	1	195.9×	0.059	BMP4
negative regulation of mRNA modification	1	195.9×	0.059	ADARB2
cellular response to salt	1	195.9×	0.059	XPO1
positive regulation of primary miRNA processing	1	195.9×	0.059	BMP4
regulation of SREBP signaling pathway	1	195.9×	0.059	AMFR
negative regulation of T cell mediated immunity	1	130.6×	0.059	DUSP22
purine nucleotide metabolic process	1	130.6×	0.059	FHIT

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 48

Druggability breadth: 11 of 53 evidence-associated genes (21%) 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
XPO1	SELINEXOR
CYP2E1	PAZOPANIB
DDX1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK13	20	3
XPO1	4	4
CYP2E1	3	4
DDX1	2	4
FHIT	1	3
BMP15	0	0
BMP4	0	0
VLDLR	0	0
TSHZ2	0	0
AVEN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELINEXOR	4	XPO1
ZAFIRLUKAST	4	XPO1
PAZOPANIB	4	CYP2E1
PONATINIB	4	DDX1
DINACICLIB	3	CDK13
LINIFANIB	3	CDK13
DEFACTINIB	3	CDK13
FASUDIL	3	CDK13
ALVOCIDIB	3	CDK13
LESTAURTINIB	3	CDK13
CONTEZOLID	3	CYP2E1
SURAMIN	3	FHIT
VERDINEXOR	2	XPO1
DORAMAPIMOD	2	CDK13
FORETINIB	2	CDK13
DEFOSBARASERTIB	2	CDK13
RAVOXERTINIB	2	CDK13
RG-547	2	CDK13
AT-7519	2	CDK13
ISTISOCICLIB	2	CDK13
INDIRUBIN	2	CDK13
DITIOCARB	2	CYP2E1
MOLIBRESIB	2	DDX1
AS-602868	1	XPO1
PF-00562271	1	CDK13
PHA-793887	1	CDK13
AMG-900	1	CDK13
BMS-387032	1	CDK13
RGB-286638	1	CDK13
AST-487	1	CDK13

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
CYP2E1	393	ADMET:388, Binding:5
CDK13	257	Binding:250, Functional:7
XPO1	146	Binding:146
APC	24	Binding:24
FHIT	21	Binding:19, ADMET:2
DUSP22	19	Binding:19
DDX1	13	Binding:12, ADMET:1
ARSA	4	Binding:3, Functional:1
GPR37L1	3	Binding:2, Functional:1
BMP4	2	Binding:2
KBTBD12	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP10B	7.6.2.1	P-type phospholipid transporter
CDK13	2.7.11.22, 2.7.11.23	cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
FHIT	3.6.1.29	bis(5’-adenosyl)-triphosphatase
AMFR	2.3.2.27	RING-type E3 ubiquitin transferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
XPO1	146
CDK13	257
CYP2E1	393

Pharmacogenomics

Cohort genes with a PharmGKB record: 45; 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)
SELINEXOR	4	XPO1
ZAFIRLUKAST	4	XPO1
PAZOPANIB	4	CYP2E1
PONATINIB	4	DDX1
DINACICLIB	3	CDK13
LINIFANIB	3	CDK13
DEFACTINIB	3	CDK13
FASUDIL	3	CDK13
ALVOCIDIB	3	CDK13
LESTAURTINIB	3	CDK13
CONTEZOLID	3	CYP2E1
SURAMIN	3	FHIT
VERDINEXOR	2	XPO1
DORAMAPIMOD	2	CDK13
FORETINIB	2	CDK13
DEFOSBARASERTIB	2	CDK13
RAVOXERTINIB	2	CDK13
RG-547	2	CDK13
AT-7519	2	CDK13
ISTISOCICLIB	2	CDK13
INDIRUBIN	2	CDK13
DITIOCARB	2	CYP2E1
MOLIBRESIB	2	DDX1
AS-602868	1	XPO1
PF-00562271	1	CDK13
PHA-793887	1	CDK13
AMG-900	1	CDK13
BMS-387032	1	CDK13
RGB-286638	1	CDK13
AST-487	1	CDK13

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	XPO1, CYP2E1, DDX1
B	Phased (≥1) drug, not yet approved	2	CDK13, FHIT
C	Druggable family + PDB, no drug	6	DUSP22, CD1E, DUSP19, FZD6, ARSA, NCAM2
D	Druggable family + AlphaFold only, no drug	3	ADAMTSL3, GPR37L1, OR51B5
E	Difficult family or no structure, no drug	39	BMP15, BMP4, VLDLR, TSHZ2, AVEN, ATP10B, ABHD2, FAM120B, CPEB1, ADARB2 (+29 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP15	0	—
BMP4	2	—
VLDLR	0	—
TSHZ2	0	—
AVEN	0	—
ATP10B	0	—
ADAMTSL3	0	—
GPR37L1	3	—
DUSP22	19	—
CD1E	0	—
ABHD2	0	—
DUSP19	0	—
OR51B5	0	—
FAM120B	0	—
CPEB1	0	—
ADARB2	0	—
CNTLN	0	—
ERI1	0	—
BCAP29	0	—
AHCTF1	0	—
PNPLA4	0	—
CCDC148	0	—
KBTBD12	1	—
DENND6A	0	—
GXYLT1	0	—
GADL1	0	—
DIAPH2	0	—
GPBP1L1	0	—
DLC1	0	—
CCSER1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice