MAMLD1

Summary

MAMLD1 (mastermind like domain containing 1, HGNC:2568) is a protein-coding gene on chromosome Xq28, encoding Mastermind-like domain-containing protein 1 (Q13495). Transactivates the HES3 promoter independently of NOTCH proteins.

This gene encodes a mastermind-like domain containing protein. This protein may function as a transcriptional co-activator. Mutations in this gene are the cause of X-linked hypospadias type 2. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10046 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypospadias 2, X-linked (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 288 total — 9 pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_005491

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2568
Approved symbol	MAMLD1
Name	mastermind like domain containing 1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	CG1, F18
Ensembl gene	ENSG00000013619
Ensembl biotype	protein_coding
OMIM	300120
Entrez	10046

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262858, ENST00000358892, ENST00000370401, ENST00000426613, ENST00000432680, ENST00000464149, ENST00000468306, ENST00000682016, ENST00000682253, ENST00000683453, ENST00000683696, ENST00000902930, ENST00000902931, ENST00000902932, ENST00000967604

RefSeq mRNA: 7 — MANE Select: NM_005491 NM_001177465, NM_001177466, NM_001400512, NM_001400513, NM_001400514, NM_001400515, NM_005491

CCDS: CCDS14693, CCDS55525, CCDS55526, CCDS94682, CCDS94683, CCDS94684

Canonical transcript exons

ENST00000370401 — 8 exons

Exon	Start	End
ENSE00001404723	150445454	150445612
ENSE00001632259	150503274	150503517
ENSE00001700964	150462772	150462846
ENSE00001804175	150473680	150473802
ENSE00002261000	150363317	150363530
ENSE00002313574	150469745	150471490
ENSE00003574853	150509962	150510046
ENSE00003916044	150512004	150514173

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 91.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4572 / max 69.0160, expressed in 1334 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197960	1.7338	992
197961	1.5365	795
197959	0.6520	206
197963	0.2791	153
197962	0.2356	121
197964	0.0202	6

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.22	gold quality
right ovary	UBERON:0002118	88.05	gold quality
right testis	UBERON:0004534	86.70	gold quality
left ovary	UBERON:0002119	86.63	gold quality
left testis	UBERON:0004533	85.38	gold quality
testis	UBERON:0000473	84.63	gold quality
stromal cell of endometrium	CL:0002255	83.97	gold quality
cartilage tissue	UBERON:0002418	83.84	gold quality
ovary	UBERON:0000992	83.35	gold quality
tibial nerve	UBERON:0001323	83.03	gold quality
adenohypophysis	UBERON:0002196	82.13	gold quality
cortical plate	UBERON:0005343	81.98	gold quality
cingulate cortex	UBERON:0003027	81.97	gold quality
left uterine tube	UBERON:0001303	81.93	gold quality
anterior cingulate cortex	UBERON:0009835	81.83	gold quality
amygdala	UBERON:0001876	81.09	gold quality
sural nerve	UBERON:0015488	81.09	gold quality
cauda epididymis	UBERON:0004360	80.80	gold quality
ventricular zone	UBERON:0003053	80.51	gold quality
popliteal artery	UBERON:0002250	80.42	gold quality
tibial artery	UBERON:0007610	80.42	gold quality
pituitary gland	UBERON:0000007	79.77	gold quality
endocervix	UBERON:0000458	79.70	gold quality
right frontal lobe	UBERON:0002810	79.67	gold quality
hypothalamus	UBERON:0001898	79.19	gold quality
ganglionic eminence	UBERON:0004023	79.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.85	gold quality
nucleus accumbens	UBERON:0001882	78.84	gold quality
temporal lobe	UBERON:0001871	78.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting MAMLD1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4698	99.84	71.41	4303

Literature-anchored findings (GeneRIF, showing 24)

• identified three different nonsense mutations of CXorf6 in individuals with hypospadias (PMID:17086185)
• CXorf6 transactivates the Hes3 promoter, augments testosterone production (PMID:18162467)
• CXorf6 mutations are associated with isolated hypospadias of varying severity (PMID:18635673)
• MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period of sex development, and provide useful information for the molecular network involved in fetal testosterone production.[review] (PMID:19339788)
• mutational analysis of the MAMLD1-gene in hypospadias (PMID:20347055)
• Data suggest that MAMLD1 should be routinely sequenced in 46,XY disorders of sex development (DSD) patients with otherwise normal AR, SRD5A2 and NR5A1 genes. (PMID:22479329)
• The single-nucleotide polymorphisms of MAMLD1 bear no obvious correlation with hypospadias, and MAMLD1 is not a candidate gene in its pathogenesis in the Chinese population. (PMID:22934520)
• MAMLD1 mutations cause 46,XY disorders of sex development primarily because of compromised testosterone production around critical period for sex development; in addition, SNP in MAMLD1 may constitute a susceptibility factor for hypospadia. [REVIEW] (PMID:23044878)
• These results imply that the pathogenic events resulting from MAMLD1 mutations include splice errors. (PMID:25833151)
• MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and MAMLD1 may also have a role in adult life (PMID:26580071)
• occurrence of MAMDL1 gene polymorphisms, specially of c.2960C>T in 3’ UTR of its exon 7 is associated with a higher risk of isolated hypospadias in Indian children, probably by lowering androgenic levels (PMID:26815876)
• Study provides evidence that MAMLD1 transcription is up-regulated in patients with 46,XX testicular and ovotesticular disorders of sex development. (PMID:27490115)
• By direct sequencing of PCR products, we assessed and found mutations that occur in 220 sporadic cases of hypospadias. The mutation p.N589S (c.1766A>G) was found at a significantly higher rate among patients with hypospadias. (PMID:28199199)
• Attenuation of MAMLD1 Expression Suppresses the Growth and Migratory Properties of Gonadotroph Pituitary Adenomas. (PMID:30911995)
• Nuclear localization of Yes associated protein 1 (YAP1)-mastermind like domain containing 1 (MAMLD1) protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. (PMID:31477715)
• Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome. (PMID:31924698)
• Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature. (PMID:32690052)
• Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance. (PMID:33424767)
• [Advance in research on the role of MAMLD1 gene in disorders of sex development]. (PMID:34487543)
• The genomic profiling and MAMLD1 expression in human and canines with Cushing’s disease. (PMID:34517852)
• MAMLD1 and Differences/Disorders of Sex Development: An Update. (PMID:34695834)
• Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway. (PMID:36898841)
• Deletion of the F18 (MAMLD1) and MTM1 genes in two patients with congenital myopathy and hypospadias (PMID:8789451)
• The identification and genomic characterization of the F18 (MAMLD1) gene in human (PMID:9169146)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mamld1	ENSMUSG00000059401

Protein

Protein identifiers

Mastermind-like domain-containing protein 1 — Q13495 (reviewed: Q13495)

Alternative names: F18, Protein CG1

All UniProt accessions (6): Q13495, A0A804HJ96, A0A804HJD4, A0A804HKM8, A0A8C8KAR0, F8WAK3

UniProt curated annotations — full annotation on UniProt →

Function. Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.

Disease relevance. Hypospadias 2, X-linked (HYSP2) [MIM:300758] A common malformation in which the urethra opens on the ventral side of the penis, due to developmental arrest of urethral fusion. The opening can be located glandular, penile, or even more posterior in the scrotum or perineum. Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome and Opitz syndrome. The disease is caused by variants affecting the gene represented in this entry.

Induction. By NR5A1.

Similarity. Belongs to the mastermind family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13495-1	1	yes
Q13495-3	2
Q13495-4	3

RefSeq proteins (7): NP_001170936, NP_001170937, NP_001387441, NP_001387442, NP_001387443, NP_001387444, NP_005482* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026131	MAMLD1	Family

UniProt features (24 total): region of interest 7, sequence conflict 5, compositionally biased region 4, sequence variant 3, splice variant 2, chain 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13495-F1	44.08	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 676

Mutagenesis-validated functional residues (1):

Position	Phenotype
176	reduces transcriptional activation of the hes3 promoter.

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-8941856	RUNX3 regulates NOTCH signaling
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-186712	Regulation of beta-cell development
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-212436	Generic Transcription Pathway
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9012852	Signaling by NOTCH3
R-HSA-9013694	Signaling by NOTCH4

MSigDB gene sets: 212 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, REACTOME_SIGNALING_BY_NOTCH, GOBP_MALE_GAMETE_GENERATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, KOYAMA_SEMA3B_TARGETS_UP, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_SEX_DIFFERENTIATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, MODULE_20, KAYO_AGING_MUSCLE_UP, GOBP_MALE_SEX_DIFFERENTIATION, GOBP_DEVELOPMENT_OF_PRIMARY_SEXUAL_CHARACTERISTICS, GOCC_NUCLEAR_BODY

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), male gonad development (GO:0008584), spermatid differentiation (GO:0048515), spermatogenesis (GO:0007283)

GO Molecular Function (0):

GO Cellular Component (5): nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), centrosome (GO:0005813), nuclear body (GO:0016604), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by NOTCH	3
Pre-NOTCH Expression and Processing	1
Regulation of beta-cell development	1
Signaling by NOTCH1	1
Signaling by NOTCH2	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Gastrulation	1
Differentiation of T cells	1
Signal Transduction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	2
intracellular membrane-bounded organelle	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
gonad development	1
development of primary male sexual characteristics	1
spermatogenesis	1
cellular process involved in reproduction in multicellular organism	1
cell differentiation	1
male gamete generation	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
centriole	1
microtubule organizing center	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAMLD1	MTM1	Q13496	908
MAMLD1	MTMR1	Q13613	875
MAMLD1	SIRAL1	Q9BPY3	815
MAMLD1	AR	P10275	745
MAMLD1	ZFTA	C9JLR9	738
MAMLD1	SRD5A2	P31213	719
MAMLD1	HSD17B3	P37058	608
MAMLD1	DGKK	Q5KSL6	586
MAMLD1	MAML3	Q96JK9	546
MAMLD1	NR5A1	Q13285	543
MAMLD1	HES3	Q5TGS1	504
MAMLD1	AKR1D1	P51857	502
MAMLD1	MTMR2	Q13614	492
MAMLD1	HSD3B2	P26439	485
MAMLD1	YAP1	P46937	482

IntAct

2 interactions, top by confidence:

A	B	Type	Score
YES1	MAMLD1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (8): MAMLD1 (Two-hybrid), MAMLD1 (Affinity Capture-RNA), MAMLD1 (Proximity Label-MS), MAMLD1 (Proximity Label-MS), MAMLD1 (Proximity Label-MS), MAMLD1 (Proximity Label-MS), MAMLD1 (Proximity Label-MS), MAMLD1 (Proximity Label-MS)

ESM2 similar proteins: A0A1L8GR68, A0JNC2, A2AFR3, A2AQ25, F7AQ22, I3LHS8, O00472, P0C6S7, P18625, P97432, Q13495, Q14596, Q14CM0, Q15032, Q3SYW5, Q3UKU1, Q4R3X1, Q4R8G4, Q5EA15, Q5F3F2, Q5R413, Q5RD40, Q5RDJ2, Q5T5P2, Q5ZM71, Q69Z61, Q6P2K3, Q70E73, Q7Z6G8, Q80TM6, Q80XA6, Q86YP4, Q8BIZ1, Q8CHY6, Q8IZD4, Q8N228, Q8NA72, Q8NEM7, Q8NFH8, Q8QFX1

Diamond homologs: A5D7F6, Q13495, Q6T264, Q8IZL2, P0C6A2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

288 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	0
Uncertain significance	96
Likely benign	31
Benign	27

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
11611	NM_005491.5(MAMLD1):c.589G>T (p.Glu197Ter)	Pathogenic
11612	NM_005491.5(MAMLD1):c.808C>T (p.Gln270Ter)	Pathogenic
11613	NM_005491.5(MAMLD1):c.2176C>T (p.Arg726Ter)	Pathogenic
1352623	NM_005491.5(MAMLD1):c.1441C>T (p.Arg481Ter)	Pathogenic
3243921	NC_000023.10:g.(?149613783)(149840068_?)del	Pathogenic
3243933	NC_000023.10:g.(?149613783)(149767170_?)del	Pathogenic
431447	NM_005491.5(MAMLD1):c.394G>T (p.Glu132Ter)	Pathogenic
4712382	NM_005491.5(MAMLD1):c.373del (p.Ala125fs)	Pathogenic
988423	NM_005491.5(MAMLD1):c.1033del (p.Ser345fs)	Pathogenic

SpliceAI

2163 predictions. Top by Δscore:

Variant	Effect	Δscore
X:150387099:A:AG	acceptor_gain	1.0000
X:150471486:GACAG:G	donor_gain	1.0000
X:150471491:G:C	donor_loss	1.0000
X:150471492:T:A	donor_loss	1.0000
X:150509960:A:AG	acceptor_gain	1.0000
X:150509961:G:GA	acceptor_gain	1.0000
X:150509961:GCAA:G	acceptor_gain	1.0000
X:150511999:T:G	acceptor_gain	1.0000
X:150512002:A:AG	acceptor_gain	1.0000
X:150512003:G:GG	acceptor_gain	1.0000
X:150512003:GCC:G	acceptor_gain	1.0000
X:150363526:GCACG:G	donor_gain	0.9900
X:150469741:ACAG:A	acceptor_gain	0.9900
X:150469742:CAGGG:C	acceptor_loss	0.9900
X:150469743:A:AG	acceptor_gain	0.9900
X:150469743:AG:A	acceptor_gain	0.9900
X:150469744:G:GT	acceptor_gain	0.9900
X:150469744:GG:G	acceptor_gain	0.9900
X:150469744:GGGAA:G	acceptor_gain	0.9900
X:150471491:G:GG	donor_gain	0.9900
X:150473803:G:GG	donor_gain	0.9900
X:150509956:GTTTA:G	acceptor_loss	0.9900
X:150509958:TTAGC:T	acceptor_loss	0.9900
X:150509960:A:AT	acceptor_loss	0.9900
X:150509961:G:GC	acceptor_loss	0.9900
X:150509961:GC:G	acceptor_gain	0.9900
X:150509961:GCA:G	acceptor_gain	0.9900
X:150510042:TGAAG:T	donor_loss	0.9900
X:150510043:GAAGG:G	donor_loss	0.9900
X:150510044:AAG:A	donor_loss	0.9900

AlphaMissense

5048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:150470121:T:C	L183P	0.999
X:150470109:T:C	L179P	0.998
X:150470100:T:C	L176P	0.997
X:150470112:T:C	L180P	0.997
X:150470493:T:C	L307P	0.996
X:150470474:T:A	W301R	0.993
X:150470474:T:C	W301R	0.993
X:150470497:G:C	K308N	0.993
X:150470497:G:T	K308N	0.993
X:150470121:T:A	L183H	0.990
X:150470100:T:A	L176H	0.989
X:150470476:G:C	W301C	0.988
X:150470476:G:T	W301C	0.988
X:150470493:T:A	L307Q	0.987
X:150470169:T:A	I199K	0.986
X:150470169:T:C	I199T	0.986
X:150471207:T:C	L545S	0.986
X:150469828:G:C	R85S	0.985
X:150469828:G:T	R85S	0.985
X:150471202:G:C	K543N	0.985
X:150471202:G:T	K543N	0.985
X:150470966:A:C	S465R	0.984
X:150470968:C:A	S465R	0.984
X:150470968:C:G	S465R	0.984
X:150470121:T:G	L183R	0.983
X:150470484:C:A	A304D	0.983
X:150469836:T:A	L88H	0.982
X:150470493:T:G	L307R	0.982
X:150471215:T:C	F548L	0.980
X:150471217:T:A	F548L	0.980

dbSNP variants (sampled 300 via entrez): RS1000020087 (X:150372382 G>A), RS1000042822 (X:150434741 A>G,T), RS1000057657 (X:150444763 A>G), RS1000208295 (X:150478115 A>C,T), RS1000548849 (X:150476212 T>C), RS1000649383 (X:150417253 T>C,G), RS1000725631 (X:150408139 G>A), RS1000767766 (X:150398367 G>A,T), RS1000798633 (X:150459492 C>T), RS1000826816 (X:150492507 C>T), RS1000866597 (X:150372654 T>C), RS1000884078 (X:150426089 G>A), RS1000936857 (X:150467825 T>A), RS1000942620 (X:150492167 G>A,T), RS1001116822 (X:150365686 C>T)

Disease associations

OMIM: gene MIM:300120 | disease phenotypes: MIM:300758, MIM:310400

GenCC curated gene-disease

Disease	Classification	Inheritance
hypospadias 2, X-linked	Strong	X-linked

Mondo (5): hypospadias 2, X-linked (MONDO:0010423), 46,XY ovotesticular disorder of sex development (MONDO:0017968), disorder of sexual differentiation (MONDO:0002145), prostate cancer (MONDO:0008315), X-linked myotubular myopathy (MONDO:0010683)

Orphanet (5): OBSOLETE: Familial hypospadias (Orphanet:440), 46,XY ovotesticular difference of sex development (Orphanet:325345), Difference of sex development (Orphanet:90771), Familial prostate cancer (Orphanet:1331), X-linked centronuclear myopathy (Orphanet:596)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000776	Congenital diaphragmatic hernia
HP:0000807	Glanular hypospadias
HP:0000808	Penoscrotal hypospadias
HP:0000818	Abnormality of the endocrine system
HP:0000883	Thin ribs
HP:0001290	Generalized hypotonia
HP:0001382	Joint hypermobility
HP:0001419	X-linked recessive inheritance
HP:0001518	Small for gestational age
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0002023	Anal atresia
HP:0002032	Esophageal atresia
HP:0002093	Respiratory insufficiency
HP:0003244	Penile hypospadias
HP:0003577	Congenital onset
HP:0008226	Androgen insufficiency
HP:0008722	Urethral diverticulum
HP:0011968	Feeding difficulties
HP:0012435	Ventral shortening of foreskin
HP:0040314	Blind vagina
HP:0100627	Displacement of the urethral meatus

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001538_6	Immune reponse to smallpox (secreted IFN-alpha)	6.000000e-10
GCST010002_97	Refractive error	6.000000e-11
GCST90002383_139	Hematocrit	2.000000e-12
GCST90002384_520	Hemoglobin	6.000000e-10
GCST90002401_294	Platelet distribution width	9.000000e-18
GCST90002403_721	Red blood cell count	3.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007984	platelet component distribution width
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C567462	Hypospadias 2, X-Linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects expression	4
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Doxorubicin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol A	decreases expression	1
tobacco tar	decreases expression, decreases reaction	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	increases expression	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	increases expression	1
Gasoline	decreases expression, increases abundance, affects cotreatment	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer