IL17RD

Summary

IL17RD (interleukin 17 receptor D, HGNC:17616) is a protein-coding gene on chromosome 3p14.3, encoding Interleukin-17 receptor D (Q8NFM7). Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation.

This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. The encoded protein is a component of the interleukin-17 receptor signaling complex, and the interaction between this protein and IL-17R does not require the interleukin. The gene product also affects fibroblast growth factor signaling, inhibiting or stimulating growth through MAPK/ERK signaling. Alternate splicing generates multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 54756 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kallmann syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 315 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_017563

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17616
Approved symbol	IL17RD
Name	interleukin 17 receptor D
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	SEF, IL17RLM, FLJ35755, IL-17RD
Ensembl gene	ENSG00000144730
Ensembl biotype	protein_coding
OMIM	606807
Entrez	54756

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000296318, ENST00000320057, ENST00000463523, ENST00000467210, ENST00000469841, ENST00000479825, ENST00000498471, ENST00000914043, ENST00000914044, ENST00000914045

RefSeq mRNA: 2 — MANE Select: NM_017563 NM_001318864, NM_017563

CCDS: CCDS2880, CCDS82790

Canonical transcript exons

ENST00000296318 — 13 exons

Exon	Start	End
ENSE00000966783	57097596	57098538
ENSE00000966784	57089982	57096505
ENSE00001280152	57165161	57165353
ENSE00003499729	57106110	57106154
ENSE00003507927	57114692	57114817
ENSE00003514729	57102479	57102589
ENSE00003522529	57110193	57110311
ENSE00003534291	57109537	57109657
ENSE00003581379	57104342	57104407
ENSE00003605003	57103091	57103145
ENSE00003605153	57101179	57101363
ENSE00003621884	57105857	57106008
ENSE00003690693	57120256	57120313

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 96.57.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4821 / max 242.6256, expressed in 829 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42641	2.4813	641
42640	1.8665	448
42642	1.1343	433

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.57	gold quality
oocyte	CL:0000023	94.76	gold quality
mammary duct	UBERON:0001765	93.16	gold quality
epithelium of mammary gland	UBERON:0003244	93.06	gold quality
ganglionic eminence	UBERON:0004023	92.89	gold quality
embryo	UBERON:0000922	92.88	gold quality
corpus epididymis	UBERON:0004359	92.64	gold quality
cauda epididymis	UBERON:0004360	92.56	gold quality
parietal pleura	UBERON:0002400	92.16	gold quality
cortical plate	UBERON:0005343	91.64	gold quality
germinal epithelium of ovary	UBERON:0001304	91.12	gold quality
sperm	CL:0000019	89.74	gold quality
ventricular zone	UBERON:0003053	88.43	gold quality
mammary gland	UBERON:0001911	87.50	gold quality
tendon of biceps brachii	UBERON:0008188	87.41	gold quality
thoracic mammary gland	UBERON:0005200	87.39	gold quality
endothelial cell	CL:0000115	87.36	gold quality
kidney epithelium	UBERON:0004819	86.45	gold quality
saphenous vein	UBERON:0007318	86.08	gold quality
myometrium	UBERON:0001296	85.60	gold quality
caput epididymis	UBERON:0004358	85.51	gold quality
pigmented layer of retina	UBERON:0001782	85.39	gold quality
skin of hip	UBERON:0001554	85.20	gold quality
calcaneal tendon	UBERON:0003701	85.17	gold quality
tendon	UBERON:0000043	85.08	gold quality
layer of synovial tissue	UBERON:0007616	85.06	gold quality
visceral pleura	UBERON:0002401	84.32	gold quality
adult organism	UBERON:0007023	83.30	gold quality
body of uterus	UBERON:0009853	82.59	gold quality
smooth muscle tissue	UBERON:0001135	82.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

221 targeting IL17RD, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 29)

• Sef exerts its inhibitory effects at the level of FGFR and upstream of Ras providing an additional level of negative regulation of FGF signaling (PMID:12604616)
• human SEF is likely to play critical roles in endothelial or epithelial functions such as proliferation, migration, and angiogenesis (PMID:12807873)
• CUG codon functions as a major translation initiation site in the alternatively spliced transcript variant hSef-b. (PMID:14742870)
• HSef acts as a spatial regulator for ERK signaling by targeting ERK to the cytoplasm. (PMID:15239952)
• Sef binds to TAK1 and has a role in JNK activation and apoptosis (PMID:15277532)
• Sef is downregulated in advanced prostate cancer and might facilitate an enhanced tumorigenic response to FGFs (PMID:16474841)
• Sef inhibited FGF induced, but not RasG12V mediated, signal transduction. We propose that Sef interacted with Ras in the inhibition of Ras/MAPK signaling pathway. (PMID:16859641)
• hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling (PMID:17035228)
• Inhibitory effect of hSef on cell proliferation combined with consistent downregulation in human carcinoma indicates a tumor suppressor-like role for Sef. (PMID:17420726)
• Sef plays a positive role in the EGF/EGFR-mediated MAPK signaling pathway. (PMID:18096367)
• IL 17RD protein is a part of the Interleukin-17 receptor signaling complex, therefore providing novel evidence for Interleukin-17 signaling through a heteromeric and/or homomeric receptor complex. (PMID:19079364)
• Findings indicate that Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef. (PMID:22298595)
• The expression of hSef is decreased in epithelial ovarian carcinoma tissue, but the expression of FGF-2 is increased. (PMID:22335910)
• This study establishes Sef as a feedback antagonist of proinflammatory cytokines and highlights its potential to regulate the crosstalk between proinflammatory cytokine receptors and receptor tyrosine kinases. (PMID:22975329)
• Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia. (PMID:23047677)
• Downregulation of SEF mRNA is associated with prostate cancer. (PMID:23169297)
• FGF17 and IL17RD prpopsed as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in congenital hypogonadotropic hypogonadism. (PMID:23643382)
• These results reveal Sef-S actives Lys63-linked TAK1 polyubiquitination on lysine 209, induces TAK1-mediated JNK and p38 activation and also results apoptosis in 293T cells. (PMID:23770285)
• Downregulation of Dusp6, Sprouty4, and Sef–negative modulators of FGF2/ERK1/2 signaling–was present in eutopic endometria of adenomyosis, which may play critical roles in the development of adenomyosis. (PMID:24681741)
• Demonstrate SEF expression in a healthy ovary during folliculogenesis and suggest hormonal regulation of its expression may be an important factor involved in intra-ovarian control mechanisms. (PMID:25118304)
• IL17RD negatively regulates Toll-like receptor (TLR)-induced responses. (PMID:25808990)
• Low SEF expression is associated with Epithelial-Mesenchymal Transition in Breast Cancer and thus Metastasis in breast Cancer. (PMID:26950413)
• Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. (PMID:28073170)
• miR-193a-3p is downregulated in ulcerative colitis neoplasia, and its loss promotes carcinogenesis through upregulation of IL17RD. These findings provide novel insight into inflammation-driven colorectal cancer and could suggest new therapeutic targets in this high-risk population (PMID:28600480)
• This study provides new insights into structure-function relation of Sef protein and the molecular mechanism by which Sef serves to limit classical NF-kappaB transcriptional activity. (PMID:30862497)
• MAPK signaling dependency in epithelial lung cancer cells is due to the scaffold protein interleukin-17 receptor D (IL17RD), which is directly repressed by ZEB1. (PMID:30867319)
• Elevation of circ-PITX1 upregulates interleukin 17 receptor D expression via sponging miR-518a-5p and facilitates cell progression in glioma. (PMID:31069865)
• IL-17RD is a functional receptor for IL-17A in vitro and in vivo and mediates the proinflammatory gene expression downstream of IL-17A.. (PMID:31175175)
• Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism. (PMID:32389901)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	il17rd	ENSDARG00000098359
mus_musculus	Il17rd	ENSMUSG00000040717
rattus_norvegicus	Il17rd	ENSRNOG00000021966

Paralogs (4): IL17RB (ENSG00000056736), IL17RE (ENSG00000163701), IL17RC (ENSG00000163702), IL17RA (ENSG00000177663)

Protein

Protein identifiers

Interleukin-17 receptor D — Q8NFM7 (reviewed: Q8NFM7)

Alternative names: IL17Rhom, Interleukin-17 receptor-like protein, Sef homolog

All UniProt accessions (2): Q8NFM7, C9J6R0

UniProt curated annotations — full annotation on UniProt →

Function. Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation. Regulates the nuclear ERK signaling pathway by spatially blocking nuclear translocation of activated ERK without inhibiting cytoplasmic phosphorylation of ERK. Mediates JNK activation and may be involved in apoptosis. May inhibit FGF-induced FGFR1 tyrosine phosphorylation. Might have a role in the early stages of fate specification of GnRH-secreting neurons. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.

Subunit / interactions. Interacts with MAP3K7. Self-associates. Interacts with FGFR1, FGFR2 and phosphorylated MAP2K1 or MAP2K2. Associates with a MAP2K1/2-MAPK1/3 complex.

Subcellular location. Golgi apparatus membrane. Cell membrane Cytoplasm.

Tissue specificity. Expressed in umbilical vein endothelial cells and in several highly vascularized tissues such as kidney, colon, skeletal muscle, heart and small intestine. Highly expressed in ductal epithelial cells of salivary glands, seminal vesicles and the collecting tubules of the kidney. Isoform 1 is also highly expressed in both fetal and adult brain, pituitary, tonsils, spleen, adenoids, fetal kidney, liver, testes and ovary. Isoform 1 is also expressed at moderate levels in primary aortic endothelial cells and adrenal medulla, and at low levels in adrenal cortex. Isoform 4 is specifically and highly expressed in pituitary, fetal brain and umbilical vein endothelial cells.

Disease relevance. Hypogonadotropic hypogonadism 18 with or without anosmia (HH18) [MIM:615267] 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 distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in IL17RD also have a heterozygous mutation in another HH-associated gene including FGFR1 and KISS1R.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NFM7-1	1, hSef-a, IL17RLM-L, Long	yes
Q8NFM7-2	2, IL17RLM-S, Short
Q8NFM7-3	3
Q8NFM7-4	4, hSef-b

RefSeq proteins (2): NP_001305793, NP_060033* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013568	SEFIR_dom	Domain
IPR031951	IL17R_D_N	Domain
IPR035897	Toll_tir_struct_dom_sf	Homologous_superfamily
IPR039465	IL-17_rcpt-like	Family

Pfam: PF08357, PF16742

UniProt features (31 total): sequence variant 9, glycosylation site 8, splice variant 3, topological domain 2, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFM7-F1	69.68	0.36

Functional residue map

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

Glycosylation sites (8): 55, 62, 80, 137, 171, 206, 277, 19

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5674135	MAP2K and MAPK activation

MSigDB gene sets: 229 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER, RICKMAN_HEAD_AND_NECK_CANCER_A, GOBP_RESPONSE_TO_GROWTH_FACTOR, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN

GO Biological Process (3): negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), cytokine-mediated signaling pathway (GO:0019221)

GO Molecular Function (2): interleukin-17 receptor activity (GO:0030368), protein binding (GO:0005515)

GO Cellular Component (6): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RAF/MAP kinase cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cytokine receptor activity	1
interleukin-17 binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
nuclear lumen	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL17RD	IL17RA	Q96F46	982
IL17RD	IL17RC	Q8NAC3	979
IL17RD	IL17RB	Q9NRM6	959
IL17RD	IL17RE	Q8NFR9	959
IL17RD	SPRY4	Q9C004	868
IL17RD	IL17B	Q9UHF5	852
IL17RD	IL17C	Q9P0M4	805
IL17RD	IL17D	Q8TAD2	784
IL17RD	IL25	Q9H293	780
IL17RD	IL17F	Q96PD4	774
IL17RD	PTP4A2	Q12974	768
IL17RD	PTP4A1	Q93096	761
IL17RD	IL17A	Q16552	722
IL17RD	HS6ST1	O60243	700
IL17RD	FGF8	P55075	670

IntAct

7 interactions, top by confidence:

A	B	Type	Score
IL17RD	RRN3	psi-mi:“MI:0915”(physical association)	0.560
IL17RD	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
IL17RD	PTPRD	psi-mi:“MI:0914”(association)	0.350
RRN3	POLR1G	psi-mi:“MI:0914”(association)	0.350
IL17RD	FBXW11	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): IL17RD (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), BTRC (Affinity Capture-MS), FBXW11 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), RELT (Affinity Capture-MS), IL17RD (Affinity Capture-Western), Fgfr1 (Affinity Capture-Western), Fgfr2 (Affinity Capture-Western), IL17RD (Affinity Capture-RNA), IL17RD (Synthetic Lethality), IL17RD (Two-hybrid), IL17RD (Proximity Label-MS), IL17RD (Affinity Capture-RNA), RELT (Affinity Capture-MS)

ESM2 similar proteins: A1L4K1, D4A7V9, E9QHE3, F1LW30, H0UZ81, O15344, O70583, O95361, P82457, P82458, P97573, Q14258, Q14596, Q28CB1, Q38HM4, Q3UMR0, Q3V3A7, Q58D15, Q5F479, Q5R760, Q5RC94, Q5REJ9, Q5REW9, Q5RF77, Q5XIH6, Q61510, Q6P549, Q6P6S3, Q6UXZ4, Q7T2L7, Q7TNH6, Q7Z494, Q80VK6, Q80WG7, Q8BZ52, Q8JZL1, Q8K1S2, Q8NFM7, Q91Z63, Q969Q1

Diamond homologs: Q7T2L7, Q8JZL1, Q8NFM7, Q8QHJ9, Q96F46, Q60943

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	173
Likely benign	77
Benign	32

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
50870	NM_017563.5(IL17RD):c.1403C>T (p.Ser468Leu)	Pathogenic
50871	NM_017563.5(IL17RD):c.1730C>A (p.Pro577Gln)	Pathogenic
180146	NM_017563.5(IL17RD):c.600G>A (p.Trp200Ter)	Likely pathogenic
4277795	NM_017563.5(IL17RD):c.1358C>T (p.Ala453Val)	Likely pathogenic
545109	NM_017563.5(IL17RD):c.676G>A (p.Gly226Ser)	Likely pathogenic

SpliceAI

1648 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57097598:AGG:A	donor_gain	1.0000
3:57101175:GCACC:G	donor_loss	1.0000
3:57101176:CA:C	donor_loss	1.0000
3:57101177:ACC:A	donor_loss	1.0000
3:57101360:TTTT:T	acceptor_gain	1.0000
3:57101369:T:TC	acceptor_gain	1.0000
3:57102474:GATA:G	donor_loss	1.0000
3:57102475:ATAC:A	donor_loss	1.0000
3:57102476:TACCT:T	donor_loss	1.0000
3:57102477:A:C	donor_loss	1.0000
3:57102585:GTGCA:G	acceptor_gain	1.0000
3:57102586:TGCA:T	acceptor_gain	1.0000
3:57102587:GCA:G	acceptor_gain	1.0000
3:57102588:CA:C	acceptor_gain	1.0000
3:57102588:CAC:C	acceptor_gain	1.0000
3:57102590:C:CC	acceptor_gain	1.0000
3:57103087:CTACC:C	donor_loss	1.0000
3:57103089:ACC:A	donor_loss	1.0000
3:57103090:C:CT	donor_loss	1.0000
3:57103090:CCTGG:C	donor_gain	1.0000
3:57103141:ACCAG:A	acceptor_gain	1.0000
3:57103142:CCAG:C	acceptor_gain	1.0000
3:57103142:CCAGC:C	acceptor_gain	1.0000
3:57103143:CAG:C	acceptor_gain	1.0000
3:57103143:CAGC:C	acceptor_gain	1.0000
3:57103143:CAGCT:C	acceptor_loss	1.0000
3:57103144:AG:A	acceptor_gain	1.0000
3:57103145:GCTG:G	acceptor_loss	1.0000
3:57103146:C:A	acceptor_loss	1.0000
3:57103146:C:CC	acceptor_gain	1.0000

AlphaMissense

4856 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57102523:G:T	A312E	0.999
3:57102541:G:C	P306R	0.999
3:57102553:G:T	A302D	0.999
3:57106004:C:A	W200C	0.999
3:57106004:C:G	W200C	0.999
3:57106006:A:G	W200R	0.999
3:57106006:A:T	W200R	0.999
3:57110248:C:G	C125S	0.999
3:57110249:A:G	C125R	0.999
3:57110249:A:T	C125S	0.999
3:57110287:C:G	R112P	0.999
3:57114710:A:G	W98R	0.999
3:57114710:A:T	W98R	0.999
3:57098087:C:T	G539D	0.998
3:57098435:G:A	S423F	0.998
3:57102517:G:T	A314E	0.998
3:57102535:A:T	V308E	0.998
3:57102538:A:C	L307R	0.998
3:57102541:G:T	P306Q	0.998
3:57102547:G:T	T304K	0.998
3:57102550:A:T	I303N	0.998
3:57106151:C:T	C185Y	0.998
3:57110294:C:G	G110R	0.998
3:57110294:C:T	G110R	0.998
3:57114815:A:G	C63R	0.998
3:57101201:A:G	L381P	0.997
3:57101222:A:T	V374D	0.997
3:57102514:G:T	T315K	0.997
3:57102532:A:T	V309D	0.997
3:57102544:A:T	V305E	0.997

dbSNP variants (sampled 300 via entrez): RS1000025275 (3:57125218 C>T), RS1000048625 (3:57095407 C>G), RS1000058913 (3:57167540 G>A), RS1000110814 (3:57097532 A>C), RS1000137570 (3:57149870 C>T), RS1000216609 (3:57127940 C>T), RS1000268762 (3:57127592 G>T), RS1000278622 (3:57149560 G>A), RS1000313543 (3:57169754 AGAGGGCT>A), RS1000346371 (3:57167968 T>C), RS1000368584 (3:57140544 T>C), RS1000375486 (3:57155596 A>T), RS1000388440 (3:57112676 A>G), RS1000445572 (3:57161926 G>A,C), RS1000450805 (3:57119551 G>C)

Disease associations

OMIM: gene MIM:606807 | disease phenotypes: MIM:615267, MIM:108010, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
Kallmann syndrome	Supportive	Autosomal dominant
hypogonadotropic hypogonadism 18 with or without anosmia	Limited	Autosomal dominant

Mondo (5): hypogonadotropic hypogonadism 18 with or without anosmia (MONDO:0014103), hypogonadism (MONDO:0002146), arteriovenous malformations of the brain (MONDO:0007154), hypogonadotropic hypogonadism (MONDO:0018555), Kallmann syndrome (MONDO:0018800)

Orphanet (3): Kallmann syndrome (Orphanet:478), Brain arteriovenous malformation (Orphanet:46724), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000830	Anterior hypopituitarism
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_2732	Blood protein levels	9.000000e-37
GCST008839_479	Height	8.000000e-10

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007006	Hypogonadism	C19.391.482
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-17 receptor family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression, increases methylation	5
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
methylmercuric chloride	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
benzo(e)pyrene	increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	increases expression	1
(+)-JQ1 compound	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cadmium	increases abundance, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	decreases expression	1
Progesterone	affects cotreatment, decreases expression	1
Dronabinol	increases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT00194675	PHASE4	COMPLETED	TRADE-Testosterone Replacement and Dutasteride Effectiveness
NCT00240981	PHASE4	TERMINATED	TOM: Testosterone in Older Men With Sarcopenia
NCT00287586	PHASE4	COMPLETED	Testosterone Replacement in Older Men and Atherosclerosis Progression
NCT00304213	PHASE4	WITHDRAWN	Does Testosterone Improve Function in Hypogonadal Older Men
NCT00349362	PHASE4	COMPLETED	Testosterone for Men With Insulin Treated Type 2 Diabetes
NCT00421460	PHASE4	COMPLETED	The Therapy of Nebido as Mono or in Combination With PDE-5 Inhibitors in Hypogonadal Patients With Erectile Dysfunction
NCT00440440	PHASE4	WITHDRAWN	Effect of Testosterone Gel Replacement on Fat Mass in Males With Low Testosterone Levels and Diabetes
NCT00487734	PHASE4	COMPLETED	Effect of Testosterone Replacement on Insulin Resistance
NCT00504712	PHASE4	COMPLETED	Testosterone for Peripheral Vascular Disease
NCT00700024	PHASE4	UNKNOWN	Odense Androgen Study - The Effect of Testim and Training in Hypogonadal Men
NCT00710827	PHASE4	WITHDRAWN	Nebido Versus Placebo in Elderly Men With Typical Symptoms of Late Onset Hypogonadism Over a Period of 54 Weeks
NCT00752869	PHASE4	COMPLETED	Efficacy Study for Use of Dutasteride (Avodart) With Testosterone Replacement
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01084369	PHASE4	TERMINATED	Effect of Testosterone on Endothelial Function and Microcirculation in Type 2 Diabetic Patients With Hypogonadism
NCT01092858	PHASE4	TERMINATED	NEBIDO in Symptomatic Late Onset Hypogonadism (SLOH)
NCT01107067	PHASE4	COMPLETED	Testosterone Replacement Therapy Decreases Plasma Paraoxonase 1 Enzyme Activity In Male Patients With Hypogonadism
NCT01123278	PHASE4	COMPLETED	Testosterone Replacement in Metabolic Syndrome and Inflammation
NCT01127659	PHASE4	COMPLETED	Testosterone Replacement in Men With Diabetes and Obesity
NCT01160341	PHASE4	COMPLETED	Metabolic Syndrome Criteria and the Effect of Testosterone Treatment in Young Men With Hypogonadism
NCT01560546	PHASE4	COMPLETED	Testosterone Therapy of Men With Type 2 Diabetes Mellitus (T2DM)
NCT01689896	PHASE4	WITHDRAWN	Testosterone and Pain Sensitivity
NCT01748370	PHASE4	COMPLETED	Vitamin D Treatment and Hypogonadism in Men
NCT01893281	PHASE4	COMPLETED	The Effect of Testosterone Topical Solution (LY900011) in Hypogonadal Men With Suboptimal Response to a Topical Testosterone Gel
NCT02102646	PHASE4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02111434	PHASE4	COMPLETED	Visceral Adiposity Index and Triglyceride/High-density Lipoprotein Cholesterol Ratio in the Congenital Hypogonadotropic Hypogonadism and Effect of Testosteron Treatment
NCT02111473	PHASE4	COMPLETED	The Effect of Testosteron Replacement Treatment on the Fibroblast Growth Factor-23, Asymmetric Dimethylarginine and Vitamin D Levels in the Congenital Hypogonadotropic Hypogonadism
NCT02366975	PHASE4	COMPLETED	TRT on BPH Hypoganadal MetS Patients. Florence-PROTEST
NCT02433730	PHASE4	COMPLETED	Testosterone Therapy in Hypogonadal Men Treated With Opioids
NCT02937740	PHASE4	COMPLETED	Open-Label Study, Evaluating Patient Satisfaction and Symptom Improvement When Treating Male Hypogonadism With Natesto™
NCT02959853	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)
NCT03057899	PHASE4	COMPLETED	Efficacy of Fenugreek Seed and Lespedeza Cuneata in TDS
NCT03126656	PHASE4	COMPLETED	Effects of Testosterone on Myocardial Repolarization
NCT03518034	PHASE4	COMPLETED	A Study to Evaluate the Effect of Testosterone Replacement Therapy (TRT) on the Incidence of Major Adverse Cardiovascular Events (MACE) and Efficacy Measures in Hypogonadal Men
NCT03619330	PHASE4	COMPLETED	Testosterone Replacement Therapy and Liraglutide Effects on Weight Loss in Hypogonadism.
NCT03887936	PHASE4	COMPLETED	Testosterone Therapy and Bone Quality in Men With Diabetes and Hypogonadism
NCT04274894	PHASE4	COMPLETED	A Study of the Effect of Topical Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT04320745	PHASE4	COMPLETED	A Study to Evaluate Androderm®’s Effect on Blood Pressure in Adult Hypogonodal Male Participants