WDR11

Summary

WDR11 (WD repeat domain 11, HGNC:13831) is a protein-coding gene on chromosome 10q26.12, encoding WD repeat-containing protein 11 (Q9BZH6). Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis.

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene is located in the chromosome 10q25-26 region, which is frequently deleted in gliomas and tumors of other tissues, and is disrupted by the t(10;19) translocation rearrangement in glioblastoma cells. The gene location suggests that it is a candidate gene for the tumor suppressor locus.

Source: NCBI Gene 55717 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 14 with or without anosmia (Strong, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 536 total — 7 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 3
• MANE Select transcript: NM_018117

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13831
Approved symbol	WDR11
Name	WD repeat domain 11
Location	10q26.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1351, FLJ10506, WDR15, HH14, DR11, SRI1
Ensembl gene	ENSG00000120008
Ensembl biotype	protein_coding
OMIM	606417
Entrez	55717

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding_CDS_not_defined, 2 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000263461, ENST00000462529, ENST00000470052, ENST00000478567, ENST00000497136, ENST00000603658, ENST00000604220, ENST00000604509, ENST00000604585, ENST00000604714, ENST00000605069, ENST00000605178, ENST00000605202, ENST00000605320, ENST00000605376, ENST00000605543, ENST00000605659

RefSeq mRNA: 1 — MANE Select: NM_018117 NM_018117

CCDS: CCDS7619

Canonical transcript exons

ENST00000263461 — 29 exons

Exon	Start	End
ENSE00001098644	120867066	120867169
ENSE00001312477	120908556	120909524
ENSE00003468517	120880826	120880901
ENSE00003470816	120900029	120900137
ENSE00003472788	120889895	120890009
ENSE00003478301	120871170	120871346
ENSE00003482419	120903055	120903232
ENSE00003486960	120902257	120902322
ENSE00003500308	120883780	120883888
ENSE00003501729	120858643	120858796
ENSE00003505317	120852524	120852635
ENSE00003530536	120865047	120865212
ENSE00003537838	120904047	120904142
ENSE00003538997	120860109	120860282
ENSE00003543527	120904646	120904811
ENSE00003551900	120862735	120862921
ENSE00003559173	120906776	120906855
ENSE00003560278	120865630	120865744
ENSE00003564091	120905319	120905416
ENSE00003579112	120851362	120851506
ENSE00003593933	120878353	120878459
ENSE00003614318	120890716	120890887
ENSE00003621926	120901036	120901098
ENSE00003625722	120866569	120866764
ENSE00003632149	120885814	120885938
ENSE00003646513	120873839	120873923
ENSE00003648150	120886689	120886836
ENSE00003661654	120889078	120889184
ENSE00003677831	120905876	120906021

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 96.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5397 / max 371.1609, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107378	29.8430	1821
107380	3.6205	593
107377	0.9041	568
107376	0.8410	536
206014	0.3311	163

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	96.17	gold quality
nasopharynx	UBERON:0001728	96.15	gold quality
calcaneal tendon	UBERON:0003701	96.06	gold quality
choroid plexus epithelium	UBERON:0003911	95.84	gold quality
germinal epithelium of ovary	UBERON:0001304	95.34	gold quality
oocyte	CL:0000023	95.13	gold quality
adrenal tissue	UBERON:0018303	95.04	gold quality
visceral pleura	UBERON:0002401	94.96	gold quality
monocyte	CL:0000576	94.91	gold quality
secondary oocyte	CL:0000655	94.86	gold quality
mononuclear cell	CL:0000842	94.77	gold quality
leukocyte	CL:0000738	94.49	gold quality
right uterine tube	UBERON:0001302	94.32	gold quality
parietal pleura	UBERON:0002400	94.24	gold quality
pleura	UBERON:0000977	94.02	gold quality
corpus callosum	UBERON:0002336	94.01	gold quality
endothelial cell	CL:0000115	93.59	gold quality
right ovary	UBERON:0002118	93.52	gold quality
body of pancreas	UBERON:0001150	93.27	gold quality
left lobe of thyroid gland	UBERON:0001120	93.19	gold quality
right lobe of thyroid gland	UBERON:0001119	93.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.08	gold quality
thyroid gland	UBERON:0002046	93.06	gold quality
metanephros cortex	UBERON:0010533	92.96	gold quality
tonsil	UBERON:0002372	92.92	gold quality
body of uterus	UBERON:0009853	92.78	gold quality
amniotic fluid	UBERON:0000173	92.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.68	gold quality
cerebellar hemisphere	UBERON:0002245	92.66	gold quality
left ovary	UBERON:0002119	92.65	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.43
E-MTAB-2983	no	806.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RARA

miRNA regulators (miRDB)

75 targeting WDR11, 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-3163	100.00	77.23	8605
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 10)

• Represents a candidate gene for the frequently proposed tumor suppressor gene in 10q25-26, which is involved in tumorigenesis of glial and other tumors showing frequent alterations in the distal 10q region. (PMID:11536051)
• This gene is expressed on chromosome 10p26. (PMID:12684685)
• Data show that the HTPAPL-WDR11-FGFR2 locus was more susceptible to recombination than to nucleotide substitution. (PMID:12684693)
• WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome, causing impaired pubertal development. (PMID:20887964)
• Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at the trans-Golgi Network To Promote Virus Replication. (PMID:26178983)
• WDR11 genetic mutation is responsible for the pathophysiology of pituitary stalk interruption syndrome. (PMID:28453858)
• Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum. (PMID:29263200)
• Data indicate a functional link between adaptor protein complex 1 (AP-1) and the WD repeat protein 11 (WDR11) complex. (PMID:29426865)
• Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability. (PMID:34413497)
• Common and Distinct Genetic Architecture of Age at Diagnosis of Diabetes in South Indian and European Populations. (PMID:37308106)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr11	ENSDARG00000075245
mus_musculus	Wdr11	ENSMUSG00000042055
rattus_norvegicus	Wdr11	ENSRNOG00000020430
caenorhabditis_elegans	Y110A7A.9	WBGENE00022459

Protein

Protein identifiers

WD repeat-containing protein 11 — Q9BZH6 (reviewed: Q9BZH6)

Alternative names: Bromodomain and WD repeat-containing protein 2, WD repeat-containing protein 15

All UniProt accessions (4): Q9BZH6, S4R3P9, S4R3Z0, S4R451

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis. Regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotropin-releasing hormone production. WDR11 complex facilitates the tethering of Adaptor protein-1 complex (AP-1)-derived vesicles. WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1.

Subunit / interactions. Component of the complex WDR11 composed of C17orf75, FAM91A1 and WDR11; FAM91A1 and WDR11 are required for proper location of the complex. Interacts (via the N-terminal and the central portion of the protein) with EMX1. Interacts with GLI3; the interaction associateS EMX1 with GLI3. Interacts with TBC1D23; this interaction may be indirect and recruits TBC1D23 to AP-1-derived vesicles.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium basal body. Nucleus. Cilium axoneme. Cytoplasmic vesicle. Golgi apparatus. trans-Golgi network.

Tissue specificity. Ubiquitous.

Disease relevance. A chromosomal aberration involving WDR11 is found in a form of glioblastoma. Translocation t(10;19)(q26;q13.3) with ZNF320. A chromosomal aberration involving WDR11 is found in a form of Kallmann syndrome. Translocation 46,XY,t(10;12)(q26.12;q13.11). Hypogonadotropic hypogonadism 14 with or without anosmia (HH14) [MIM:614858] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, autosomal recessive 78 (MRT78) [MIM:620237] An autosomal recessive neurodevelopmental disorder characterized by usually mild intellectual disability, microcephaly, and short stature. Additional features may include ocular abnormalities and mild skeletal defects. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_060587* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR039694	WDR11	Family
IPR057852	Beta-prop_WDR11_1st	Domain
IPR057853	Beta-prop_WDR11_2nd	Domain
IPR057854	TPR_WDR11	Domain

Pfam: PF23751, PF23752, PF23753

UniProt features (128 total): strand 65, helix 27, turn 14, repeat 9, sequence variant 8, modified residue 4, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8Z9M	ELECTRON MICROSCOPY	3.3
8XFB	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZH6-F1	83.75	0.51

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 (4): 205, 209, 402, 406

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013407	RHOH GTPase cycle

MSigDB gene sets: 410 (showing top): GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_GROWTH, GOBP_VESICLE_TARGETING, TATTATA_MIR374, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_205, GOCC_TRANS_GOLGI_NETWORK, GOBP_CILIUM_ORGANIZATION, GOBP_MULTICELLULAR_ORGANISM_GROWTH, GOBP_ORGANELLE_ASSEMBLY, KIM_GERMINAL_CENTER_T_HELPER_UP, GOBP_REGULATION_OF_SMOOTHENED_SIGNALING_PATHWAY

GO Biological Process (7): intracellular protein transport (GO:0006886), heart development (GO:0007507), regulation of smoothened signaling pathway (GO:0008589), multicellular organism growth (GO:0035264), cilium assembly (GO:0060271), head development (GO:0060322), obsolete vesicle tethering to Golgi (GO:0099041)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (18): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), trans-Golgi network (GO:0005802), centriole (GO:0005814), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), ciliary basal body (GO:0036064), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cytoplasm	3
intracellular membrane-bounded organelle	2
microtubule organizing center	2
intracellular membraneless organelle	2
cytoskeleton	2
sperm flagellum	2
intracellular protein localization	1
protein transport	1
intracellular transport	1
animal organ development	1
circulatory system development	1
smoothened signaling pathway	1
regulation of signal transduction	1
multicellular organismal process	1
developmental growth	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
anatomical structure development	1
binding	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
Golgi apparatus subcompartment	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
microtubule	1
ciliary plasm	1
intracellular vesicle	1
cilium	1
endomembrane system	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR11	TOR1A	O14656	784
WDR11	TNFRSF25	P78507	774
WDR11	TNFRSF10A	O00220	768
WDR11	C17orf75	Q9HAS0	720
WDR11	HLA-DRB1	P01911	694
WDR11	Q5Y7H0	Q5Y7H0	608
WDR11	TOR1B	O14657	593
WDR11	TNFRSF21	O75509	544
WDR11	HLA-A	P01891	507
WDR11	HLA-DQB1	P01917	480
WDR11	HLA-B	P01889	478
WDR11	HLA-DPB1	P01916	474
WDR11	TNFRSF10B	O14763	435
WDR11	DR1	Q01658	428
WDR11	NSMF	Q6X4W1	424

IntAct

94 interactions, top by confidence:

A	B	Type	Score
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
COPRS	PRMT5	psi-mi:“MI:0914”(association)	0.770
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
ZNF397	ZNF197	psi-mi:“MI:0914”(association)	0.530
ALDH1L2	WDR11	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
RNF19B	PIK3R2	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
C17orf75	FAM91A1	psi-mi:“MI:0914”(association)	0.530
SV2A	EXTL3	psi-mi:“MI:0914”(association)	0.530
WDR11	EMX1	psi-mi:“MI:0915”(physical association)	0.500
GLI3	EMX1	psi-mi:“MI:0914”(association)	0.500
GLI3	WDR11	psi-mi:“MI:0915”(physical association)	0.500
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
	ANKRD28	psi-mi:“MI:0914”(association)	0.350
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
UBXN7	PJA2	psi-mi:“MI:0914”(association)	0.350
UBXN7	UBR5	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (176): WDR11 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), WDR11 (Affinity Capture-MS), NAA40 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Co-fractionation), WDR11 (Affinity Capture-MS), WDR11 (Proximity Label-MS)

ESM2 similar proteins: A0A0R4IC37, A1A4K3, A2CEI4, B1WC10, E9PY46, F1QEB7, F4IDS7, O08658, O13046, O75694, O75717, O95876, P33194, P37199, P59328, Q08D69, Q10569, Q10570, Q16531, Q32NR9, Q3U1J4, Q4ADV7, Q566H4, Q5DQR4, Q5R649, Q5U1Z0, Q5ZLG9, Q6P6Z0, Q6PGF3, Q6PJI9, Q7XWP1, Q802U2, Q805F9, Q8BMG7, Q8C0M0, Q8C456, Q8CEC0, Q8CJF7, Q8K1X1, Q8NFP9

Diamond homologs: F1QEB7, Q8K1X1, Q9BZH6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHOJ GTPase cycle	5	12.5×	4e-03
Membrane Trafficking	10	4.6×	4e-03
Vesicle-mediated transport	10	4.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	9
Uncertain significance	243
Likely benign	120
Benign	137

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1098849	NM_018117.12(WDR11):c.1255C>T (p.Gln419Ter)	Pathogenic
1098850	NM_018117.12(WDR11):c.2931+1G>A	Pathogenic
1098851	NM_018117.12(WDR11):c.1439del (p.Asn480fs)	Pathogenic
2067762	NM_018117.12(WDR11):c.1280T>G (p.Leu427Ter)	Pathogenic
2103265	NM_018117.12(WDR11):c.1153del (p.Leu385fs)	Pathogenic
4759346	NM_018117.12(WDR11):c.949C>T (p.Arg317Ter)	Pathogenic
68840	NM_018117.12(WDR11):c.2070T>A (p.His690Gln)	Pathogenic
1687367	NM_018117.12(WDR11):c.163dup (p.Gln55fs)	Likely pathogenic
2005976	NM_018117.12(WDR11):c.3292-1G>C	Likely pathogenic
2631485	NM_018117.12(WDR11):c.352+1G>A	Likely pathogenic
3061804	NM_018117.12(WDR11):c.3220_3223del (p.Asp1074fs)	Likely pathogenic
3338568	NM_018117.12(WDR11):c.3141dup (p.Ser1048fs)	Likely pathogenic
4293190	NM_018117.12(WDR11):c.879+1G>T	Likely pathogenic
4538418	NM_018117.12(WDR11):c.458G>A (p.Trp153Ter)	Likely pathogenic
4849292	NM_018117.12(WDR11):c.1748del (p.Leu583fs)	Likely pathogenic
928566	NM_018117.12(WDR11):c.1849G>T (p.Glu617Ter)	Likely pathogenic

SpliceAI

5223 predictions. Top by Δscore:

Variant	Effect	Δscore
10:120851546:G:GT	donor_gain	1.0000
10:120851547:A:T	donor_gain	1.0000
10:120858640:CA:C	acceptor_loss	1.0000
10:120858641:A:AT	acceptor_loss	1.0000
10:120858642:G:GT	acceptor_loss	1.0000
10:120858762:GT:G	donor_gain	1.0000
10:120858795:GG:G	donor_gain	1.0000
10:120858796:GG:G	donor_gain	1.0000
10:120858803:A:T	donor_gain	1.0000
10:120858815:GCTAA:G	donor_gain	1.0000
10:120858816:C:G	donor_gain	1.0000
10:120860096:C:A	acceptor_gain	1.0000
10:120860097:G:A	acceptor_gain	1.0000
10:120860215:G:GT	donor_gain	1.0000
10:120860224:C:G	donor_gain	1.0000
10:120860232:A:G	donor_gain	1.0000
10:120862733:A:AG	acceptor_gain	1.0000
10:120862734:G:GG	acceptor_gain	1.0000
10:120865045:A:AG	acceptor_gain	1.0000
10:120865046:G:GA	acceptor_gain	1.0000
10:120865046:GT:G	acceptor_gain	1.0000
10:120865046:GTGCT:G	acceptor_gain	1.0000
10:120865210:CAGG:C	donor_loss	1.0000
10:120865211:AGGT:A	donor_loss	1.0000
10:120865212:GGTA:G	donor_loss	1.0000
10:120865213:G:T	donor_loss	1.0000
10:120865214:T:G	donor_loss	1.0000
10:120866555:A:AG	acceptor_gain	1.0000
10:120867064:A:AG	acceptor_gain	1.0000
10:120867065:G:GG	acceptor_gain	1.0000

AlphaMissense

7999 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:120858649:T:A	W69R	1.000
10:120858649:T:C	W69R	1.000
10:120860117:T:A	W121R	1.000
10:120860117:T:C	W121R	1.000
10:120860186:T:A	W144R	1.000
10:120860186:T:C	W144R	1.000
10:120878363:T:A	W523R	1.000
10:120878363:T:C	W523R	1.000
10:120885817:T:A	W618R	1.000
10:120885817:T:C	W618R	1.000
10:120885819:G:C	W618C	1.000
10:120885819:G:T	W618C	1.000
10:120886793:T:A	V693D	1.000
10:120889108:T:A	W718R	1.000
10:120889108:T:C	W718R	1.000
10:120889145:G:T	G730V	1.000
10:120889159:T:A	W735R	1.000
10:120889159:T:C	W735R	1.000
10:120890779:T:A	W803R	1.000
10:120890779:T:C	W803R	1.000
10:120904126:T:C	L1004P	1.000
10:120904656:C:A	A1013D	1.000
10:120904668:T:C	L1017P	1.000
10:120904713:T:C	L1032P	1.000
10:120904718:G:C	A1034P	1.000
10:120904719:C:A	A1034D	1.000
10:120904721:T:C	C1035R	1.000
10:120904722:G:A	C1035Y	1.000
10:120904723:T:G	C1035W	1.000
10:120904769:A:G	K1051E	1.000

dbSNP variants (sampled 300 via entrez): RS1000042154 (10:120879141 A>G,T), RS1000071216 (10:120889584 G>T), RS1000079809 (10:120886939 G>A), RS1000242200 (10:120905795 A>C), RS1000261118 (10:120860632 T>A), RS1000275630 (10:120881914 T>G), RS1000445862 (10:120898852 T>C,G), RS1000446524 (10:120885592 C>T), RS1000469987 (10:120854296 A>G), RS1000507620 (10:120862847 C>T), RS1000582026 (10:120882317 A>G), RS1000633871 (10:120904402 A>C), RS1000716392 (10:120856488 C>G,T), RS1000764052 (10:120863194 C>A,T), RS1000798005 (10:120908336 G>A)

Disease associations

OMIM: gene MIM:606417 | disease phenotypes: MIM:620237, MIM:614858, MIM:146110, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 14 with or without anosmia	Strong	Autosomal dominant
intellectual developmental disorder, autosomal recessive 78	Strong	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant

Mondo (9): microcephaly (MONDO:0001149), intellectual developmental disorder, autosomal recessive 78 (MONDO:0859373), hypogonadotropic hypogonadism 14 with or without anosmia (MONDO:0013926), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism (MONDO:0018555), CHARGE syndrome (MONDO:0008965), hereditary breast ovarian cancer syndrome (MONDO:0003582), Kallmann syndrome (MONDO:0018800)

Orphanet (4): Kallmann syndrome (Orphanet:478), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), CHARGE syndrome (Orphanet:138), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000141	Amenorrhea
HP:0000044	Hypogonadotropic hypogonadism

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
tetrabromobisphenol A	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
K 7174	increases expression	1
bisphenol B	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Ivermectin	decreases expression	1
Lead	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)