FLRT3

Summary

FLRT3 (fibronectin leucine rich transmembrane protein 3, HGNC:3762) is a protein-coding gene on chromosome 20p12.1, encoding Leucine-rich repeat transmembrane protein FLRT3 (Q9NZU0). Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners.

This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. FLRTs may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. This gene is expressed in many tissues. Two alternatively spliced transcript variants encoding the same protein have been described for this gene.

Source: NCBI Gene 23767 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kallmann syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 108 total — 2 pathogenic
• Phenotypes (HPO): 56
• MANE Select transcript: NM_198391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3762
Approved symbol	FLRT3
Name	fibronectin leucine rich transmembrane protein 3
Location	20p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125848
Ensembl biotype	protein_coding
OMIM	604808
Entrez	23767

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000341420, ENST00000378053, ENST00000462077, ENST00000874852, ENST00000874853, ENST00000963260, ENST00000963261, ENST00000963262

RefSeq mRNA: 2 — MANE Select: NM_198391 NM_013281, NM_198391

CCDS: CCDS13121

Canonical transcript exons

ENST00000341420 — 3 exons

Exon	Start	End
ENSE00001377241	14337404	14337612
ENSE00001383817	14329134	14329327
ENSE00001422543	14322985	14327558

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5905 / max 356.8898, expressed in 1094 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186477	6.5927	926
186478	3.9819	738
186479	2.0159	647

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.34	gold quality
lower lobe of lung	UBERON:0008949	97.22	gold quality
pericardium	UBERON:0002407	97.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.96	gold quality
middle temporal gyrus	UBERON:0002771	95.93	gold quality
renal medulla	UBERON:0000362	95.86	gold quality
visceral pleura	UBERON:0002401	95.05	gold quality
germinal epithelium of ovary	UBERON:0001304	94.62	gold quality
jejunal mucosa	UBERON:0000399	93.61	gold quality
hair follicle	UBERON:0002073	93.41	gold quality
caput epididymis	UBERON:0004358	93.27	gold quality
seminal vesicle	UBERON:0000998	92.94	gold quality
trigeminal ganglion	UBERON:0001675	92.25	gold quality
cerebellar vermis	UBERON:0004720	91.86	gold quality
renal glomerulus	UBERON:0000074	91.61	gold quality
metanephric glomerulus	UBERON:0004736	91.38	gold quality
dorsal root ganglion	UBERON:0000044	90.94	gold quality
pleura	UBERON:0000977	90.80	gold quality
kidney epithelium	UBERON:0004819	90.67	gold quality
corpus epididymis	UBERON:0004359	90.00	gold quality
urethra	UBERON:0000057	89.88	gold quality
parietal pleura	UBERON:0002400	89.78	gold quality
duodenum	UBERON:0002114	89.21	gold quality
metanephros	UBERON:0000081	88.97	gold quality
nipple	UBERON:0002030	88.36	gold quality
kidney	UBERON:0002113	88.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.95	gold quality
primary visual cortex	UBERON:0002436	87.35	gold quality
adult mammalian kidney	UBERON:0000082	86.86	gold quality
epithelial cell of pancreas	CL:0000083	86.78	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	1220.08
E-MTAB-6108	yes	156.16
E-HCAD-10	yes	29.50
E-ANND-3	yes	18.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

218 targeting FLRT3, 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-9-5P	100.00	72.28	2361
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-101-3P	99.94	75.03	2230
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-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

Literature-anchored findings (GeneRIF, showing 6)

• This study demonistrated that LPHN3 and its ligand FLRT3 play an important role in glutamatergic synapse development. (PMID:22405201)
• Results suggest that UNC5 and LPHN3 can simultaneously bind to FLRT3, forming a trimeric complex, and that FLRT3 may form transsynaptic complexes with both LPHN3 and UNC5. (PMID:26235030)
• Low FLRT3 expression is associated with lung graft dysfunction. (PMID:27421969)
• Variants in FLRT3 and SLC35E2B identified using exome sequencing in seven high myopia families from Central Europe. (PMID:33711669)
• TGF-beta-Induced FLRT3 Attenuation Is Essential for Cancer-Associated Fibroblast-Mediated Epithelial-Mesenchymal Transition in Colorectal Cancer. (PMID:35560224)
• FLRT3 and TGF-beta/SMAD4 signalling: Impacts on apoptosis, autophagy and ion channels in supraventricular tachycardia. (PMID:38509727)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	flrt3	ENSDARG00000076895
mus_musculus	Flrt3	ENSMUSG00000051379
rattus_norvegicus	Flrt3	ENSRNOG00000004874

Paralogs (22): DCN (ENSG00000011465), RTN4R (ENSG00000040608), ASPN (ENSG00000106819), FLRT1 (ENSG00000126500), LRRC4 (ENSG00000128594), LRRC4B (ENSG00000131409), PODNL1 (ENSG00000132000), LRTM1 (ENSG00000144771), LRRC4C (ENSG00000148948), LRRTM1 (ENSG00000162951), LRRC15 (ENSG00000172061), PODN (ENSG00000174348), LRRTM4 (ENSG00000176204), BGN (ENSG00000182492), LRRC19 (ENSG00000184434), FLRT2 (ENSG00000185070), GP1BA (ENSG00000185245), RTN4RL1 (ENSG00000185924), RTN4RL2 (ENSG00000186907), NYX (ENSG00000188937), LRRC66 (ENSG00000188993), LRRTM3 (ENSG00000198739)

Protein

Protein identifiers

Leucine-rich repeat transmembrane protein FLRT3 — Q9NZU0 (reviewed: Q9NZU0)

Alternative names: Fibronectin-like domain-containing leucine-rich transmembrane protein 3

All UniProt accessions (1): Q9NZU0

UniProt curated annotations — full annotation on UniProt →

Function. Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina. Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells. Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members. Promotes neurite outgrowth (in vitro). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length. Plays a role in the regulation of the density of glutamaergic synapses. Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning. Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development. Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development.

Subunit / interactions. Monomer and homodimer. Self-associates (via leucine-rich repeats), giving rise to homooligomers. Interacts with FGFR1. Interacts (via extracellular domain) with ADGRL1/LPHN1 and LPHN2 (via olfactomedin-like domain). Interacts (via extracellular domain) with ADGRL3 (via olfactomedin-like domain); the interaction is direct. Interacts (via extracellular domain) with UNC5B and UNC5D (via extracellular domain); the interaction is direct. Identified in complexes composed of FLRT3, ADGRL3 and UNC5B, respectively FLRT3, ADGRL3 and UNC5D. May also interact (via extracellular domain) with UNC5A and UNC5C. Interacts (via cytoplasmic domain) with ROBO1.

Subcellular location. Cell membrane. Presynaptic cell membrane. Endoplasmic reticulum membrane. Cell junction. Focal adhesion. Secreted. Cell projection. Axon. Growth cone membrane.

Tissue specificity. Expressed in kidney, brain, pancreas, skeletal muscle, lung, liver, placenta, and heart.

Post-translational modifications. N-glycosylated. Proteolytic cleavage in the juxtamembrane region gives rise to a soluble ectodomain. Cleavage is probably effected by a metalloprotease.

Disease relevance. Hypogonadotropic hypogonadism 21 with or without anosmia (HH21) [MIM:615271] 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 FLRT3 also have a mutation in another HH-associated gene including FGFR1, HS6ST1 and FGF17.

RefSeq proteins (2): NP_037413, NP_938205* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR050333	SLRP	Family

Pfam: PF13855

UniProt features (80 total): strand 15, mutagenesis site 11, repeat 10, sequence variant 8, helix 7, turn 7, sequence conflict 4, domain 3, region of interest 3, glycosylation site 3, disulfide bond 3, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6JBU	X-RAY DIFFRACTION	1.85
5CMP	X-RAY DIFFRACTION	2.6
5CMN	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZU0-F1	74.57	0.52

Functional residue map

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

Disulfide bonds (3): 31–37, 35–44, 309–334

Glycosylation sites (3): 226, 282, 296

Mutagenesis-validated functional residues (11):

Position	Phenotype
38	abolishes adgrl3 binding; when associated with a-43; a-45 and a-47.
43	abolishes adgrl3 binding; when associated with a-64. abolishes adgrl3 binding; when associated with a-38; a-43 and a-47.
45	abolishes adgrl3 binding; when associated with a-38; a-43 and a-47.
47	abolishes adgrl3 binding; when associated with a-38; a-43 and a-45.
64	abolishes adgrl3 binding; when associated with a-43.
89	abolishes adgrl3 binding; when associated with a-91.
91	abolishes adgrl3 binding; when associated with a-89.
181	no effect on homodimerization; when associated with a-183.
181	adds a glycosylation site that strongly reduces homodimerization; when associated with t-183.
183	no effect on homodimerization; when associated with a-181.
183	adds a glycosylation site that strongly reduces homodimerization; when associated with t-183.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-376176	Signaling by ROBO receptors
R-HSA-5654687	Downstream signaling of activated FGFR1

MSigDB gene sets: 435 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GGGNRMNNYCAT_UNKNOWN, GCANCTGNY_MYOD_Q6, REACTOME_SIGNALING_BY_FGFR, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_NEUROGENESIS

GO Biological Process (15): proepicardium cell migration involved in pericardium morphogenesis (GO:0003345), axon guidance (GO:0007411), synapse assembly (GO:0007416), heart development (GO:0007507), fibroblast growth factor receptor signaling pathway (GO:0008543), neuron projection development (GO:0031175), embryonic morphogenesis (GO:0048598), response to axon injury (GO:0048678), positive regulation of synapse assembly (GO:0051965), head development (GO:0060322), obsolete cell-cell adhesion via plasma-membrane adhesion molecules (GO:0098742), synaptic membrane adhesion (GO:0099560), neuron projection extension (GO:1990138), cell adhesion (GO:0007155), negative chemotaxis (GO:0050919)

GO Molecular Function (5): fibroblast growth factor receptor binding (GO:0005104), protein-macromolecule adaptor activity (GO:0030674), protein homodimerization activity (GO:0042803), chemorepellent activity (GO:0045499), protein binding (GO:0005515)

GO Cellular Component (22): obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), cell junction (GO:0030054), extracellular matrix (GO:0031012), growth cone membrane (GO:0032584), presynaptic membrane (GO:0042734), axon terminus (GO:0043679), axonal growth cone (GO:0044295), postsynaptic membrane (GO:0045211), synaptic membrane (GO:0097060), glutamatergic synapse (GO:0098978), extracellular region (GO:0005576), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), axon (GO:0030424), cell projection (GO:0042995), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Axon guidance	1
Signaling by FGFR1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
synapse organization	2
cytoplasm	2
growth cone	2
synaptic membrane	2
presynapse	2
synapse	2
pericardium morphogenesis	1
cell migration involved in heart development	1
axonogenesis	1
neuron projection guidance	1
nervous system development	1
cell junction assembly	1
animal organ development	1
circulatory system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
neuron development	1
plasma membrane bounded cell projection organization	1
anatomical structure morphogenesis	1
embryo development	1
response to wounding	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
anatomical structure development	1
cell-cell adhesion	1
developmental cell growth	1
neuron projection morphogenesis	1
developmental growth involved in morphogenesis	1
cellular process	1
chemotaxis	1
growth factor receptor binding	1
protein binding	1
molecular adaptor activity	1
identical protein binding	1
protein dimerization activity	1
receptor ligand activity	1
negative chemotaxis	1

Protein interactions and networks

STRING

1292 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLRT3	ADGRL3	Q9HAR2	969
FLRT3	MACROD2	A1Z1Q3	959
FLRT3	UNC5B	Q8IZJ1	923
FLRT3	TENM2	Q9NT68	871
FLRT3	UNC5D	Q6UXZ4	781
FLRT3	ADGRL1	O94910	733
FLRT3	ADGRL2	O95490	732
FLRT3	RND1	Q92730	684
FLRT3	UNC5A	Q6ZN44	643
FLRT3	FN1	P02751	635
FLRT3	ANOS1	P23352	592
FLRT3	IL17RD	Q8NFM7	586
FLRT3	ROBO1	Q9Y6N7	585
FLRT3	SPRY4	Q9C004	562
FLRT3	PROKR2	Q8NFJ6	555

IntAct

23 interactions, top by confidence:

A	B	Type	Score
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
FLRT3	ADGRL3	psi-mi:“MI:0407”(direct interaction)	0.620
FLRT1	TCAF2	psi-mi:“MI:0914”(association)	0.530
APP	FLRT3	psi-mi:“MI:0915”(physical association)	0.510
FLRT3	FLRT3	psi-mi:“MI:0407”(direct interaction)	0.440
FLRT3	CALR	psi-mi:“MI:0915”(physical association)	0.400
MBLAC2	STAT3	psi-mi:“MI:0914”(association)	0.350
CD81	STX3	psi-mi:“MI:0914”(association)	0.350
CD81	PVR	psi-mi:“MI:0914”(association)	0.350
CD81	CD276	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
MBLAC2	CD63	psi-mi:“MI:0914”(association)	0.350
PHB2	FLRT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): FLRT3 (Affinity Capture-MS), FLRT3 (Affinity Capture-MS), FLRT3 (Proximity Label-MS), FLRT3 (Two-hybrid), APP (Affinity Capture-Western), FLRT3 (Affinity Capture-Western), FLRT3 (Affinity Capture-MS), FLRT3 (Affinity Capture-MS), FLRT3 (Affinity Capture-MS), FLRT3 (Proximity Label-MS), FLRT3 (Proximity Label-MS), FLRT3 (Proximity Label-MS), FLRT3 (Proximity Label-MS), FLRT3 (Proximity Label-MS), FLRT3 (Proximity Label-MS)

ESM2 similar proteins: A0N0X6, A4IIW9, B0BLW3, B1H134, B1H234, B4F7C5, D3ZAL8, D3ZTV3, D4A7P2, E5DHB5, F1NUK7, F7D3V9, O43155, O43300, O94898, P58681, Q32Q07, Q3SXY7, Q3URE9, Q504C1, Q50L44, Q52KR2, Q5R482, Q5R6T0, Q5RDJ4, Q61809, Q66HV9, Q6RKD8, Q6UXK5, Q70AK3, Q7L985, Q80XG9, Q80ZD7, Q80ZD8, Q80ZD9, Q86VH4, Q86VH5, Q8BGA3, Q8BGT1, Q8BLU0

Diamond homologs: B1H134, B1H234, D3ZTV3, F1NUK7, G5EFX6, G5EG78, O43155, O88280, P19879, P20774, P24014, P58874, P79119, P83286, Q5R6T0, Q5RAC4, Q5RBL2, Q62000, Q6PEZ8, Q6RKD8, Q70AK3, Q810C1, Q8BGT1, Q8BLU0, Q8MJF1, Q96PX8, Q9DE65, Q9NR97, Q9NZU0, Q9NZU1, Q9UBM4, Q9W6H0, A8WGA3, D4ABX8, O42235, O55226, O60938, O75093, O88279, O94769

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	79
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3248347	NC_000020.10:g.(?13765715)(15124933_?)del	Pathogenic
50865	NM_198391.3(FLRT3):c.1016A>G (p.Lys339Arg)	Pathogenic

SpliceAI

659 predictions. Top by Δscore:

Variant	Effect	Δscore
20:14327556:ACCC:A	acceptor_loss	1.0000
20:14327554:GAACC:G	acceptor_gain	0.9900
20:14327557:CC:C	acceptor_gain	0.9900
20:14327558:CC:C	acceptor_gain	0.9900
20:14327559:C:CC	acceptor_gain	0.9900
20:14327569:G:C	acceptor_gain	0.9900
20:14337397:CACTT:C	donor_loss	0.9900
20:14337398:ACTTA:A	donor_loss	0.9900
20:14337399:CTTA:C	donor_loss	0.9900
20:14337400:TTA:T	donor_loss	0.9900
20:14337401:TA:T	donor_loss	0.9900
20:14337402:A:AC	donor_gain	0.9900
20:14337402:ACC:A	donor_loss	0.9900
20:14337403:C:CC	donor_gain	0.9900
20:14337403:C:CT	donor_loss	0.9900
20:14327556:ACC:A	acceptor_gain	0.9800
20:14327557:CCC:C	acceptor_gain	0.9800
20:14327559:C:T	acceptor_gain	0.9800
20:14327564:A:AC	acceptor_gain	0.9800
20:14327564:A:C	acceptor_gain	0.9800
20:14327569:G:GC	acceptor_gain	0.9800
20:14327555:AACC:A	acceptor_gain	0.9700
20:14327573:G:GC	acceptor_gain	0.9600
20:14328066:A:AC	donor_gain	0.9600
20:14330195:A:AG	acceptor_gain	0.9600
20:14337402:AC:A	donor_gain	0.9600
20:14337403:CC:C	donor_gain	0.9600
20:14327430:A:C	donor_gain	0.9500
20:14328088:G:C	donor_gain	0.9500
20:14333945:A:C	acceptor_gain	0.9500

AlphaMissense

4264 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:14326505:G:C	C334W	1.000
20:14326506:C:G	C334S	1.000
20:14326506:C:T	C334Y	1.000
20:14326507:A:G	C334R	1.000
20:14326507:A:T	C334S	1.000
20:14326580:G:C	C309W	1.000
20:14326581:C:T	C309Y	1.000
20:14326586:C:A	W307C	1.000
20:14326586:C:G	W307C	1.000
20:14326588:A:G	W307R	1.000
20:14326588:A:T	W307R	1.000
20:14326592:A:C	N305K	1.000
20:14326592:A:T	N305K	1.000
20:14326664:A:C	N281K	1.000
20:14326664:A:T	N281K	1.000
20:14326680:A:G	L276P	1.000
20:14326736:G:C	N257K	1.000
20:14326736:G:T	N257K	1.000
20:14326746:A:G	L254P	1.000
20:14326752:A:G	L252P	1.000
20:14326802:A:C	N235K	1.000
20:14326802:A:T	N235K	1.000
20:14326818:A:G	L230P	1.000
20:14326827:A:C	L227W	1.000
20:14326880:G:C	N209K	1.000
20:14326880:G:T	N209K	1.000
20:14326896:A:G	L204P	1.000
20:14326952:A:C	N185K	1.000
20:14326952:A:T	N185K	1.000
20:14326953:T:A	N185I	1.000

dbSNP variants (sampled 300 via entrez): RS1000189399 (20:14329916 A>T), RS1000422432 (20:14333187 A>G), RS1000453776 (20:14332708 C>G,T), RS1000656227 (20:14323891 C>A), RS1000722305 (20:14325782 A>C,G), RS1000752795 (20:14331740 G>A), RS1001091209 (20:14323554 C>A,T), RS1001104411 (20:14339297 A>G), RS1001368388 (20:14338016 T>C), RS1001761845 (20:14326695 C>G,T), RS1002247962 (20:14331801 G>A), RS1002401414 (20:14338454 A>G), RS1002483579 (20:14328977 G>A), RS1002497157 (20:14324635 T>C), RS1002534456 (20:14329142 A>C)

Disease associations

OMIM: gene MIM:604808 | disease phenotypes: MIM:615271

GenCC curated gene-disease

Disease	Classification	Inheritance
Kallmann syndrome	Supportive	Autosomal dominant
hypogonadotropic hypogonadism 21 with or without anosmia	Limited	Autosomal dominant

Mondo (4): hypogonadotropic hypogonadism 21 with or without anosmia (MONDO:0014107), disorder of sexual differentiation (MONDO:0002145), amenorrhea (MONDO:0001836), Kallmann syndrome (MONDO:0018800)

Orphanet (2): Kallmann syndrome (Orphanet:478), Difference of sex development (Orphanet:90771)

HPO phenotypes

56 total (30 of 56 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:0000144	Decreased fertility
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:0000789	Infertility
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
HP:0001335	Bimanual synkinesia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002864_2	Mood disorder in prion disease	7.000000e-06
GCST006585_2270	Blood protein levels	1.000000e-43
GCST011767_3	Bipolar disorder	1.000000e-09

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
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)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	4
Benzo(a)pyrene	affects expression, decreases expression, increases expression, increases methylation	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance	3
Cyclosporine	affects expression, decreases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Tretinoin	decreases expression, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, decreases expression	2
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
titanium dioxide	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
trichostatin A	decreases expression	1
methylparaben	decreases expression	1
ferrous chloride	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
XAV939	increases expression, affects binding, affects cotreatment	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Temozolomide	increases expression	1

Clinical trials (associated diseases)

62 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)
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
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00064987	PHASE2	TERMINATED	Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00392756	PHASE1	COMPLETED	Examination of Idiopathic Hypogonadotropic Hypogonadism (IHH)and Kallmann Syndrome (KS)
NCT00493961	PHASE1	COMPLETED	Studying the Effects of 7 Days of Gonadotropin Releasing Hormone (GnRH) Treatment in Men With Hypogonadism
NCT00914823	PHASE1	COMPLETED	Kisspeptin Administration in the Adult
NCT01438034	PHASE1	COMPLETED	Kisspeptin in the Evaluation of Delayed Puberty
NCT03118479	PHASE1	TERMINATED	Effect of Varying Testosterone Levels on Insulin Sensitivity in Men With Idiopathic Hypogonadotropic Hypogonadism (IHH)
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT00392457	Not specified	COMPLETED	Investigating the Regulation of Reproductive Hormones in Adult Men
NCT00494169	Not specified	COMPLETED	Investigation of the Genetic Causes of Kallmann Syndrome and Reproductive Disorders
NCT00623116	Not specified	UNKNOWN	A Study to Characterize Epidemiology, Clinical and Genetic Features of Kallmann Syndrome in Finland
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01914172	Not specified	COMPLETED	Health Needs of Patients With Kallmann Syndrome
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04733274	Not specified	ACTIVE_NOT_RECRUITING	Patient and Healthcare Professional Views on Genetic/Genomic Information and Testing
NCT05971836	Not specified	ACTIVE_NOT_RECRUITING	The Molecular Basis of Inherited Reproductive Disorders
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women