FSHB

Summary

FSHB (follicle stimulating hormone subunit beta, HGNC:3964) is a protein-coding gene on chromosome 11p14.1, encoding Follitropin subunit beta (P01225). Together with the alpha chain CGA constitutes follitropin, the follicle-stimulating hormone, and provides its biological specificity to the hormone heterodimer.

The pituitary glycoprotein hormone family includes follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone. All of these glycoproteins consist of an identical alpha subunit and a hormone-specific beta subunit. This gene encodes the beta subunit of follicle-stimulating hormone. In conjunction with luteinizing hormone, follicle-stimulating hormone induces egg and sperm production. Alternative splicing results in two transcript variants encoding the same protein.

Source: NCBI Gene 2488 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 24 without anosmia (Strong, GenCC)
• GWAS associations: 27
• Clinical variants (ClinVar): 6 total — 2 pathogenic
• Phenotypes (HPO): 30
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001382289

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3964
Approved symbol	FSHB
Name	follicle stimulating hormone subunit beta
Location	11p14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000131808
Ensembl biotype	protein_coding
OMIM	136530
Entrez	2488

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000254122, ENST00000417547, ENST00000533718

RefSeq mRNA: 3 — MANE Select: NM_001382289 NM_000510, NM_001018080, NM_001382289

CCDS: CCDS7868

Canonical transcript exons

ENST00000533718 — 3 exons

Exon	Start	End
ENSE00002182345	30231866	30232061
ENSE00002189614	30233570	30235194
ENSE00003907869	30231014	30231048

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 94.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7342 / max 2081.2746, expressed in 6 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113579	1.7222	6
113578	0.0067	2
113581	0.0038	1
113580	0.0015	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	94.33	gold quality
pituitary gland	UBERON:0000007	92.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.70	gold quality
buccal mucosa cell	CL:0002336	66.70	gold quality
pancreatic ductal cell	CL:0002079	60.01	silver quality
secondary oocyte	CL:0000655	57.93	gold quality
tibialis anterior	UBERON:0001385	57.09	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	55.50	gold quality
triceps brachii	UBERON:0001509	55.33	gold quality
inferior olivary complex	UBERON:0002127	55.32	gold quality
endothelial cell	CL:0000115	53.25	gold quality
ileal mucosa	UBERON:0000331	53.15	silver quality
nasal cavity epithelium	UBERON:0005384	52.77	gold quality
deltoid	UBERON:0001476	52.66	gold quality
tendon of biceps brachii	UBERON:0008188	52.46	gold quality
heart right ventricle	UBERON:0002080	52.23	gold quality
quadriceps femoris	UBERON:0001377	51.86	gold quality
epithelial cell of pancreas	CL:0000083	51.20	gold quality
vastus lateralis	UBERON:0001379	51.17	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
thymus	UBERON:0002370	50.25	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.64	gold quality
myocardium	UBERON:0002349	49.44	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NOTCH1	Activation

Upstream regulators (CollecTRI, top): AP1, AR, CEBPB, CREB1, CREM, DNMT1, ESR1, ESR2, FOS, FOXL2, FOXO1, GATA4, HESX1, HIF1A, ID1, ISL1, JUN, KLF6, LHX2, LHX3, LHX4, MSX1, NCOA3, NFATC4, NFYA, NR4A1, NR5A1, PAX1, PBX1, PGR, PITX1, PITX2, POU1F1, PROP1, PRRX2, RUNX2, SKIL, SMAD1, SMAD2, SMAD3

miRNA regulators (miRDB)

74 targeting FSHB, 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-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4713-5P	99.78	67.80	1794

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Review. The Asn7 and Asn24 glycosylation variants of human pituitary FSHB exhibit differential and divergent effects at the target cell level and that less sialylated, short-lived variants may exert significant effects in in vivo conditions. (PMID:11900895)
• FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia (PMID:12161499)
• Follicle-stimulating hormone interacts with exoloop 3 of the receptor. (PMID:12374801)
• A Cys82Arg mutation in this protein causes FSH deficiency in FSH levels in vitro. (PMID:12568849)
• No mutation in this gene can still cause FSH deficiency in a person with normal virilization. (PMID:12568861)
• Smad2 expression in ovarian cells requires a functional interplay between activin A (INHBA) and FSH/PKA signaling. (PMID:12665510)
• x-ray crystallographic analysis shows that the FSH beta subunit is close to the N-terminal region and the alpha subunit is projected toward exoloop 3 in the endodomain (PMID:12963710)
• pituitary exit of LH and FSH occur via different secretion pathways, and are released spatially from the pituitary via different circulatory routes. (PMID:14585810)
• LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell. (PMID:15271874)
• Sequence analysis shows that the human FSH beta gene is highly conserved and amino acid changing mutations are apparently extremely rare; only three silent polymorphisms, two of which are novel, are revealed. (PMID:16100240)
• The strategy to produce a soluble FSH-FSHR complex that involves the co-secretion of a truncated FSHR ectodomain (FSHR(HB)) and a covalently linked FSHalphabeta heterodimer, is described. (PMID:17045735)
• A major regulatory mechanism for FSH glycosylation involves control of beta-subunit N-glycosylation, possibly by inhibition of oligosaccharyl transferase. Two primate species exhibited the same all-or-none pattern of pituitary FSHbeta glycosylation. (PMID:17079072)
• There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. (PMID:17227474)
• Follitropin beta and, more precisely, follitropin alfa suppress the spectral components and power of the myoelectrical signals, which provides uterine quiescence. (PMID:18068163)
• Case Report: Isolated FSH deficiency without mutation of the FSHbeta gene and successful treatment with human menopausal gonadotropin. (PMID:18402948)
• A polymorphism within the FSHB gene is associated with serum FSH levels in men. (PMID:18567894)
• Activator protein-1 and smad proteins synergistically regulate human follicle-stimulating hormone beta-promoter activity. (PMID:18653705)
• Ghrelin suppresses the secretion of FSH in humans. (PMID:19054012)
• A novel role for FOXL2 in activin A-regulated Fshb transcription. (PMID:19324968)
• The level of serum FSH may be related to bone loss and the occurrence of osteoporosis in Chinese women. (PMID:19734592)
• This genetic marker may have clinical significance in molecular diagnostics of male reproductive success. (PMID:19897680)
• FoxL2 plays a key role in activin induction of the FSHbeta gene, by binding to sites conserved across multiple species. (PMID:20233786)
• the genomic and genetic context of the FSHB and the LHB/CGB genes largely affects the profile of the hormone production (PMID:20488225)
• FSH dysfunction due to a less acidic isoform pattern through hypoglycosylation is not a key mechanism of primary ovarian insufficiency in classic galactosemia (PMID:20814826)
• Polymorphisms in the 5’-flanking regions of FSHbeta and luteinizing hormone (LH)beta genes are probably related to the puberty onset time of Chinese Han girls. (PMID:20869425)
• Findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism. (PMID:21149714)
• [review] A middle-aged male with feminizing adrenocortical (ACC) tumor shows delayed response of luteinizing hormone and poor response of FSH to gonadotropin-releasing hormone administration. (PMID:21720063)
• We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels and affected male reproductive potential. (PMID:21733993)
• FSHB -211 TT genotype might represent a novel treatable form of male infertility characterized by severe spermatogenic impairment and low or inappropriately normal FSH plasma levels. (PMID:22000911)
• In the proposed model of the combined effects, FSHB -211G>T acts strongly on male reproductive parameters, whereas the FSHR 2039A>G effects were approximately 2-3 times smaller. (PMID:22791757)
• Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. (PMID:23015653)
• Phenotypic consequences of FSHB -211G–>T on the hypothalamic-pituitary-ovarian axis in women. (PMID:23118424)
• Both estradiol and progesterone uniquely modulate basal and GnRH-stimulated gonadotropin promoters without affecting cell growth. (PMID:23160221)
• Ser680 genotype for FSHR is a factor of relative resistance to FSH stimulation resulting in slightly higher FSH serum levels, thus leading to a prolonged duration of the menstrual cycle. (PMID:23380184)
• Data indicate that neither serum inhibin B nor follicle-stimulating hormone (FSH) is a suitable surrogate for determination of sperm concentration in a semen sample. (PMID:23423746)
• activin-regulated transcription mediated by forkhead box L2 [review] (PMID:23426431)
• Serum FSH levels are affected by the combination of genetic polymorphisms in FSHR and FSHB (PMID:23504007)
• Data suggest that low serum FSH levels in men with an SNP in promoter region of FSHB (-211G/T) result from reduced binding of LHX3 (LIM homeobox 3) to FSHB promoter/response element and down-regulation of FSHB transcription in gonadotrophs. (PMID:23766128)
• The combined effect of FSHB GG+FSHR AA may potentiate the FSH pathway, which increases serum levels of FSH and reduces antimullerian hormone in health girls. (PMID:23850305)
• 3 known FSH-action modulating SNPs (FSHB -211G/T; FSHR -29G/A, c.2039 A/G)explained together 2.3%, 1.4%, 1.0 and 1.1% of the measured variance in serum FSH, Inhibin B, testosterone and total testes volume, respectively. (PMID:24718625)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fshb	ENSMUSG00000027120
rattus_norvegicus	Fshb	ENSRNOG00000004898
drosophila_melanogaster	Gpb5	FBGN0063368

Paralogs (9): CGB2 (ENSG00000104818), LHB (ENSG00000104826), CGB3 (ENSG00000104827), TSHB (ENSG00000134200), GPHB5 (ENSG00000179600), CGB5 (ENSG00000189052), CGB7 (ENSG00000196337), CGB8 (ENSG00000213030), CGB1 (ENSG00000267631)

Protein

Protein identifiers

Follitropin subunit beta — P01225 (reviewed: P01225)

Alternative names: Follicle-stimulating hormone beta subunit, Follitropin beta chain

All UniProt accessions (2): A0A0F7RQE8, P01225

UniProt curated annotations — full annotation on UniProt →

Function. Together with the alpha chain CGA constitutes follitropin, the follicle-stimulating hormone, and provides its biological specificity to the hormone heterodimer. Binds FSHR, a G protein-coupled receptor, on target cells to activate downstream signaling pathways. Follitropin is involved in follicle development and spermatogenesis in reproductive organs.

Subunit / interactions. Heterodimer. The active follitropin is a heterodimer composed of an alpha chain/CGA shared with other hormones and a unique beta chain/FSHB shown here.

Subcellular location. Secreted.

Disease relevance. Hypogonadotropic hypogonadism 24 with or without anosmia (HH24) [MIM:229070] A form of hypogonadotropic hypogonadism, a group of disorders 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. HH24 is characterized by primary amenorrhea in women, oligo or azoospermia with low to normal testosterone levels in men, and infertility. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glycoprotein hormones subunit beta family.

RefSeq proteins (3): NP_000501, NP_001018090, NP_001369218* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001545	Gonadotropin_bsu	Family
IPR006208	Glyco_hormone_CN	Domain
IPR018245	Gonadotropin_bsu_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00007

UniProt features (21 total): strand 6, disulfide bond 6, sequence variant 2, glycosylation site 2, signal peptide 1, chain 1, mutagenesis site 1, helix 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9YXD	X-RAY DIFFRACTION	2.29
4AY9	X-RAY DIFFRACTION	2.5
8I2G	ELECTRON MICROSCOPY	2.8
4MQW	X-RAY DIFFRACTION	2.9
1XWD	X-RAY DIFFRACTION	2.92
1FL7	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01225-F1	89.32	0.75

Antibody-complex structures (SAbDab): 1 — 8I2G

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 (6): 21–69, 35–84, 38–122, 46–100, 50–102, 105–112

Glycosylation sites (2): 25, 42

Mutagenesis-validated functional residues (1):

Position	Phenotype
78	increased activation of the follicle-stimulating hormone signaling pathway.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-209822	Glycoprotein hormones
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 237 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_MALE_GAMETE_GENERATION, GOBP_KETONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_OVARIAN_FOLLICLE_DEVELOPMENT, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_OVULATION_CYCLE_PROCESS

GO Biological Process (17): progesterone biosynthetic process (GO:0006701), transforming growth factor beta receptor signaling pathway (GO:0007179), G protein-coupled receptor signaling pathway (GO:0007186), spermatogenesis (GO:0007283), female gamete generation (GO:0007292), female pregnancy (GO:0007565), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), positive regulation of steroid biosynthetic process (GO:0010893), positive regulation of cell migration (GO:0030335), follicle-stimulating hormone signaling pathway (GO:0042699), regulation of osteoclast differentiation (GO:0045670), positive regulation of bone resorption (GO:0045780), positive regulation of transcription by RNA polymerase II (GO:0045944), Sertoli cell proliferation (GO:0060011), ovarian follicle development (GO:0001541), signal transduction (GO:0007165)

GO Molecular Function (4): follicle-stimulating hormone activity (GO:0016913), signaling receptor binding (GO:0005102), hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), follicle-stimulating hormone complex (GO:0016914)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Peptide hormone biosynthesis	1
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
C21-steroid hormone biosynthetic process	1
ketone biosynthetic process	1
progesterone metabolic process	1
olefinic compound biosynthetic process	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
G protein-coupled receptor activity	1
signal transduction	1
developmental process involved in reproduction	1
male gamete generation	1
gamete generation	1
multi-organism reproductive process	1
multi-multicellular organism process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
steroid biosynthetic process	1
positive regulation of steroid metabolic process	1
positive regulation of lipid biosynthetic process	1
regulation of steroid biosynthetic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
ovarian follicle development	1
G protein-coupled receptor signaling pathway	1
ovulation cycle process	1
regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
male gonad development	1
epithelial cell proliferation	1

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSHB	FSHR	P23945	984
FSHB	GNRH1	P01148	903
FSHB	GNRHR	P30968	897
FSHB	LHCGR	P22888	896
FSHB	CGA	P01215	876
FSHB	KISS1	Q15726	798
FSHB	KISS1R	Q969F8	767
FSHB	AMH	P03971	727
FSHB	NR5A1	Q13285	725
FSHB	MPPED2	Q15777	707
FSHB	PITX1	P78337	703
FSHB	GNRH2	O43555	700
FSHB	GHRHR	Q02643	700
FSHB	PRL	P01236	688
FSHB	POMC	P01189	670

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CGA	FSHB	psi-mi:“MI:0407”(direct interaction)	0.760
FSHB	CGA	psi-mi:“MI:0915”(physical association)	0.760
FSHB	CGA	psi-mi:“MI:0407”(direct interaction)	0.760
FSHB	GPHA2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1): FSHB (Co-crystal Structure)

ESM2 similar proteins: A0A0F7YZI5, A1BN60, A1BN61, C0K3N2, O13050, O46430, O73824, P01225, P01226, P01227, P01228, P04837, P10257, P12656, P18427, P30971, P30972, P37240, P48250, P48252, P52584, Q08127, Q2PUH2, Q330K6, Q3HRV4, Q3YC02, Q52R90, Q60687, Q6EV79, Q6IY73, Q6SI68, Q6SV86, Q6U830, Q7ZZV4, Q8HY83, Q8HY84, Q8WN19, Q925Q4, Q925Q5, Q95J82

Diamond homologs: A1BN60, A1BN61, A6NKQ9, O09108, O13050, O46430, O46482, O46483, O46641, O57340, O73824, O77805, O77835, P01222, P01223, P01224, P01225, P01226, P01227, P01228, P01229, P01230, P01231, P01232, P01235, P04651, P04652, P04837, P07434, P07732, P08751, P0DN86, P0DN87, P10256, P10257, P12656, P12837, P18427, P19794, P25330

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LHX3	“up-regulates quantity by expression”	FSHB	“transcriptional regulation”
FOXO1	“down-regulates quantity by repression”	FSHB	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
376753	GRCh37/hg19 11p14.1-13(chr11:29750813-32752091)x1	Pathogenic
685976	GRCh37/hg19 11p14.1(chr11:30217030-30276703)x1	Pathogenic

SpliceAI

322 predictions. Top by Δscore:

Variant	Effect	Δscore
11:30231939:T:A	acceptor_gain	1.0000
11:30232060:GG:G	donor_gain	1.0000
11:30232061:GG:G	donor_gain	1.0000
11:30231864:A:AG	acceptor_gain	0.9900
11:30231865:G:GG	acceptor_gain	0.9900
11:30232062:G:GG	donor_gain	0.9900
11:30232063:T:G	donor_loss	0.9900
11:30231933:T:TA	acceptor_gain	0.9800
11:30231860:TCTCA:T	acceptor_gain	0.9700
11:30231861:CTCA:C	acceptor_gain	0.9700
11:30231862:TCA:T	acceptor_gain	0.9700
11:30231863:CAGTT:C	acceptor_gain	0.9700
11:30231864:AG:A	acceptor_gain	0.9700
11:30231865:G:T	acceptor_gain	0.9700
11:30231046:CAGG:C	donor_loss	0.9600
11:30231047:AGG:A	donor_loss	0.9600
11:30231049:G:GA	donor_loss	0.9600
11:30231050:T:G	donor_loss	0.9600
11:30231895:A:AG	acceptor_gain	0.9600
11:30231896:G:GG	acceptor_gain	0.9600
11:30231936:T:A	acceptor_gain	0.9600
11:30231940:G:A	acceptor_gain	0.9600
11:30232057:CCAGG:C	donor_gain	0.9600
11:30232063:TAG:T	donor_gain	0.9600
11:30233564:CCTCA:C	acceptor_loss	0.9600
11:30233566:TCAG:T	acceptor_loss	0.9600
11:30233567:CAGG:C	acceptor_loss	0.9600
11:30233569:G:T	acceptor_loss	0.9600
11:30231049:G:GG	donor_gain	0.9500
11:30232059:AGGGT:A	donor_gain	0.9500

AlphaMissense

860 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:30233690:T:G	Y94D	0.975
11:30232038:T:A	C46S	0.974
11:30232039:G:C	C46S	0.974
11:30233615:T:A	C69S	0.972
11:30233616:G:C	C69S	0.972
11:30233617:T:G	C69W	0.967
11:30232040:T:G	C46W	0.966
11:30233744:T:A	C112S	0.966
11:30233745:G:C	C112S	0.966
11:30233708:T:A	C100S	0.965
11:30233709:G:C	C100S	0.965
11:30233723:T:A	C105S	0.963
11:30233724:G:C	C105S	0.963
11:30233616:G:A	C69Y	0.961
11:30232038:T:C	C46R	0.959
11:30233700:C:A	A97D	0.959
11:30232044:G:T	G48C	0.958
11:30232052:C:G	C50W	0.957
11:30233615:T:C	C69R	0.954
11:30233616:G:T	C69F	0.953
11:30233744:T:C	C112R	0.951
11:30233708:T:C	C100R	0.949
11:30232051:G:A	C50Y	0.946
11:30232039:G:A	C46Y	0.945
11:30233746:T:G	C112W	0.945
11:30233710:T:G	C100W	0.943
11:30233723:T:C	C105R	0.943
11:30232050:T:A	C50S	0.938
11:30232051:G:C	C50S	0.938
11:30233745:G:A	C112Y	0.937

dbSNP variants (sampled 300 via entrez): RS1000001300 (11:30230732 A>G,T), RS1000065041 (11:30231407 T>C), RS1000412522 (11:30234190 T>C), RS1000435840 (11:30235410 A>G), RS1000603696 (11:30229066 A>G), RS1001057645 (11:30229410 G>C), RS1001572883 (11:30230933 G>T), RS1001899425 (11:30234876 C>T), RS1001946855 (11:30235280 G>T), RS1002901112 (11:30233341 T>C), RS1002953516 (11:30233684 T>A,C), RS1004554183 (11:30230079 T>C), RS1005356676 (11:30234823 G>A), RS1005467213 (11:30230072 C>G), RS1005660789 (11:30229690 A>C)

Disease associations

OMIM: gene MIM:136530 | disease phenotypes: MIM:194072

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 24 without anosmia	Strong	Autosomal recessive

Mondo (2): WAGR syndrome (MONDO:0008681), hypogonadotropic hypogonadism 24 without anosmia (MONDO:0009239)

Orphanet (1): WAGR syndrome (Orphanet:893)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000029	Testicular atrophy
HP:0000044	Hypogonadotropic hypogonadism
HP:0000134	Female hypogonadism
HP:0000135	Hypogonadism
HP:0000458	Anosmia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000798	Oligozoospermia
HP:0000823	Delayed puberty
HP:0000876	Oligomenorrhea
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0002750	Delayed skeletal maturation
HP:0003199	Decreased muscle mass
HP:0004408	Abnormality of the sense of smell
HP:0008213	Gonadotropin deficiency
HP:0008214	Decreased serum estradiol
HP:0008734	Decreased testicular size
HP:0010791	Hyperplasia of the Leydig cells
HP:0011462	Young adult onset
HP:0011969	Elevated circulating luteinizing hormone level
HP:0012569	Delayed menarche
HP:0012814	Bilateral breast hypoplasia
HP:0012864	Abnormal sperm morphology
HP:0030018	Decreased female libido
HP:0030341	Decreased circulating follicle stimulating hormone concentration
HP:0040171	Decreased serum testosterone concentration

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST002541_86	Menarche (age at onset)	3.000000e-08
GCST002783_605	Body mass index	5.000000e-06
GCST002925_3	Sex hormone levels	2.000000e-08
GCST002925_4	Sex hormone levels	4.000000e-09
GCST003144_4	Polycystic ovary syndrome	1.000000e-09
GCST003334_1	Length of menstrual cycle	1.000000e-16
GCST003993_6	Menarche (age at onset)	2.000000e-08
GCST004413_3	Spontaneous dizygotic twinning	1.000000e-10
GCST004549_22	Endometriosis	2.000000e-08
GCST004549_6	Endometriosis	3.000000e-08
GCST005269_3	Luteinizing hormone levels in polycystic ovary syndrome	3.000000e-16
GCST005273_5	Polycystic ovary syndrome	2.000000e-08
GCST005312_50	Menopause (age at onset)	9.000000e-14
GCST006291_10	Spherical equivalent or myopia (age of diagnosis)	2.000000e-08
GCST006958_1	Length of menstrual cycle	4.000000e-36
GCST007089_8	Polycystic ovary syndrome	9.000000e-13
GCST007280_2	Number of twin births	4.000000e-07
GCST008971_6	Urate levels	8.000000e-07
GCST008972_253	Urate levels	6.000000e-09
GCST009158_39	Uterine fibroids	6.000000e-15
GCST009391_1643	Metabolite levels	7.000000e-06
GCST009391_1647	Metabolite levels	9.000000e-06
GCST010002_234	Refractive error	2.000000e-49
GCST010178_5	Endometriosis or migraine	1.000000e-08
GCST010568_1	Polycystic ovary syndrome (indeterminate subtype)	5.000000e-12
GCST010570_5	Polycystic ovary syndrome (reproductive subtype)	9.000000e-06
GCST90044902_4	Polycystic ovary syndrome (adjusted for age)	9.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004340	body mass index
EFO:0004730	hormone measurement
EFO:0004768	follicle stimulating hormone measurement
EFO:0004704	age at menopause
EFO:0004847	age at onset
EFO:0009439	multiple births measurement
EFO:0004531	urate measurement
EFO:0007787	plasma betaine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017624	WAGR Syndrome	C04.557.435.595.950; C04.588.945.947.535.585.950; C04.700.900.950; C10.597.606.360.969; C11.250.060.950; C11.270.060.950; C11.941.375.060.950; C12.050.351.875.253.096.875; C12.050.351.937.820.535.585.950; C12.050.351.968.419.473.585.950; C12.200.706.316.096.875; C12.200.758.820.750.585.950; C12.200.777.419.473.585.950; C12.800.316.096.875; C12.900.820.535.585.950; C12.950.419.473.585.950; C12.950.983.535.585.950; C16.131.260.940; C16.131.384.079.950; C16.131.939.316.096.875; C16.320.180.940; C16.320.290.078.950; C16.320.700.900.950; C19.391.119.096.875
C537070	Follicle-stimulating hormone deficiency, isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases secretion, affects binding, affects cotreatment, increases abundance, increases chemical synthesis (+6 more)	17
Progesterone	decreases activity, increases chemical synthesis, affects abundance, increases reaction, affects cotreatment (+3 more)	17
Testosterone	affects abundance, affects cotreatment, increases chemical synthesis, increases secretion, increases abundance (+5 more)	7
Ethinyl Estradiol	affects cotreatment, affects expression, affects reaction, decreases expression	6
MOPP protocol	increases expression, affects cotreatment, affects expression	5
ABVD protocol	affects cotreatment, affects expression, increases expression	3
bisphenol A	decreases reaction, increases expression, increases secretion, affects response to substance, decreases secretion	2
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases chemical synthesis, increases expression, increases secretion, affects cotreatment	2
17 alpha-Hydroxyprogesterone Caproate	decreases expression	2
Cyclic AMP	increases abundance, increases activity, increases reaction, affects cotreatment, increases chemical synthesis (+1 more)	2
Air Pollutants	increases expression, increases abundance	2
Benzo(a)pyrene	decreases reaction, increases abundance, increases activity, increases methylation	2
Clomiphene	increases expression, increases reaction	2
Dichlorodiphenyl Dichloroethylene	increases reaction, affects cotreatment, increases activity, increases abundance	2
Estrogens, Conjugated (USP)	affects cotreatment, decreases expression	2
Naltrexone	increases expression, increases secretion	2
1-Methyl-3-isobutylxanthine	decreases reaction, increases expression	2
Levonorgestrel	affects cotreatment, affects expression, affects reaction, decreases expression	2
Cyproterone Acetate	affects cotreatment, decreases expression	2
kuntai capsule	affects cotreatment, decreases expression	1
testosterone enanthate	affects cotreatment, increases abundance	1
oxybenzone	affects response to substance, decreases secretion	1
propylparaben	decreases secretion, increases abundance	1
2,4,5-trichlorophenol	decreases secretion, affects response to substance	1
trilostane	increases abundance, affects cotreatment, decreases reaction	1
o,p’-DDT	increases abundance, increases activity, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases reaction, increases abundance	1
sodium arsenite	affects methylation	1
perfluorooctanoic acid	affects cotreatment, increases expression, increases reaction	1
dienogest	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00758108	Not specified	COMPLETED	Characterization of WAGR Syndrome and Other Chromosome 11 Gene Deletions
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06740162	Not specified	RECRUITING	Physical Activity and Community EmPOWERment Project