ANOS1

Summary

ANOS1 (anosmin 1, HGNC:6211) is a protein-coding gene on chromosome Xp22.31, encoding Anosmin-1 (P23352). Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex. It is haploinsufficient (ClinGen: sufficient evidence).

Mutations in this gene cause the X-linked Kallmann syndrome. The encoded protein is similar in sequence to proteins known to function in neural cell adhesion and axonal migration. In addition, this cell surface protein is N-glycosylated and may have anti-protease activity.

Source: NCBI Gene 3730 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 1 with or without anosmia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 572 total — 92 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 65
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000216

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6211
Approved symbol	ANOS1
Name	anosmin 1
Location	Xp22.31
Locus type	gene with protein product
Status	Approved
Aliases	KALIG-1, WFDC19
Ensembl gene	ENSG00000011201
Ensembl biotype	protein_coding
OMIM	300836
Entrez	3730

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000262648, ENST00000481896, ENST00000488294, ENST00000921740, ENST00000921741, ENST00000921742

RefSeq mRNA: 1 — MANE Select: NM_000216 NM_000216

CCDS: CCDS14130

Canonical transcript exons

ENST00000262648 — 14 exons

Exon	Start	End
ENSE00000664754	8553952	8554098
ENSE00000978149	8539664	8539758
ENSE00000978152	8534319	8534460
ENSE00001027308	8587794	8587978
ENSE00001090926	8597034	8597256
ENSE00001090928	8623608	8623670
ENSE00001090929	8570499	8570704
ENSE00001090930	8585267	8585396
ENSE00001151305	8528874	8533053
ENSE00001151308	8731830	8732137
ENSE00001306678	8536771	8536942
ENSE00001321714	8535591	8535811
ENSE00001619379	8699698	8699745
ENSE00003485006	8568232	8568376

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.71.

FANTOM5 (CAGE): breadth broad, TPM avg 6.1590 / max 142.0916, expressed in 825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198366	5.9777	820
198365	0.1813	106

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	97.71	gold quality
hair follicle	UBERON:0002073	95.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.55	gold quality
pleura	UBERON:0000977	92.84	gold quality
tibia	UBERON:0000979	92.37	gold quality
gluteal muscle	UBERON:0002000	92.03	gold quality
bronchial epithelial cell	CL:0002328	91.75	gold quality
lower lobe of lung	UBERON:0008949	91.48	gold quality
epithelium of bronchus	UBERON:0002031	91.42	gold quality
triceps brachii	UBERON:0001509	90.91	gold quality
bronchus	UBERON:0002185	90.87	gold quality
parietal pleura	UBERON:0002400	90.79	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.66	gold quality
vastus lateralis	UBERON:0001379	89.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.41	gold quality
endothelial cell	CL:0000115	89.23	gold quality
quadriceps femoris	UBERON:0001377	89.05	gold quality
biceps brachii	UBERON:0001507	89.00	gold quality
germinal epithelium of ovary	UBERON:0001304	88.91	gold quality
periodontal ligament	UBERON:0008266	88.71	gold quality
CA1 field of hippocampus	UBERON:0003881	88.58	gold quality
entorhinal cortex	UBERON:0002728	88.35	gold quality
ventricular zone	UBERON:0003053	88.11	gold quality
deltoid	UBERON:0001476	88.03	gold quality
lung	UBERON:0002048	87.68	gold quality
medulla oblongata	UBERON:0001896	87.63	gold quality
middle temporal gyrus	UBERON:0002771	87.61	gold quality
skeletal muscle tissue	UBERON:0001134	87.58	gold quality
superior vestibular nucleus	UBERON:0007227	86.77	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	58.95
E-ANND-3	yes	13.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFIA, NFIB, NFIX

miRNA regulators (miRDB)

158 targeting ANOS1, 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-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Identification of three novel mutations in the KAL1 gene in patients with Kallmann syndrome. (PMID:12050219)
• AL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling (PMID:12627230)
• six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases of Kallmann syndrome (PMID:15001591)
• it is unlikely that KAL gene mutations are a clinically significant cause of sporadic GnRH deficiency in female patients (PMID:15004876)
• anosmin-1 may modulate the catalytic activity of uPA and its signalling pathway, whereas HS determines cell surface localization of the anosmin-1-uPA complex (PMID:15324302)
• a direct action of anosmin-1 on the migratory activity of GnRH neurons is shown (PMID:15471890)
• anosmin-1 is an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines the link between autosomal and X-linked Kallmann’s syndrome (PMID:15548653)
• KAL1 gene has a closely related nonfunctional pseudogene on the Y chromosome (PMID:15636431)
• analysis of the biological function of anosmin-1 and its ability to interact with its three macromolecular ligands (PMID:15949815)
• Data suggest that the relative concentrations of Anosmin-1 and FGF-2 modulate the migration of oligodendrocyte precursors during development through their interaction with FGFR1. (PMID:16876430)
• The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic Kallmann syndrome. (PMID:17603054)
• KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. (PMID:18160472)
• 12% of Kallman syndrome males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in Idiopathic hypogonadotropic hypogonadism/Kallman syndrome. (PMID:18463157)
• binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1.FGF2.heparin complex. (PMID:19696444)
• report describes 2 intragenic deletions of KAL-1 in 2 Kallmann syndrome (KS) patients & suggests KAL-1 deletion may be more prevalent in KS patients with other congenital organ abnormalities than those described previously from Northwestern China (PMID:19734936)
• KAL1 gene expression plays an important role in cancer metastasis and protection from apoptosis. (PMID:19844165)
• Anosmin-1 produced by epidermal keratinocytes in response to calcium concentrations or cytokines may modulate epidermal nerve density in atopic dermatitis. (PMID:20219326)
• Mutations of KAL1 underlie an autosomal dominant form of Kallmann syndrome. (PMID:20362962)
• Role of the KAL1 protein missense mutations in Kallman syndrome and in olfactory bulb development. (PMID:20530987)
• Two new mutations were detected in KAL1 from male patients with idiopathic hypogonadotropic hypogonadism. (PMID:21351529)
• A central role of KAL-1, in GnRH neuron ontogeny - specifically in GnRH neuronal migration from the cribriform plate area into the brain. (PMID:21497178)
• Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes in Finland patients. (PMID:21682876)
• we report the case of a deletion of exons 4 to 14 (c.469-?_6314+?del) within the KAL1 gene in two related patients and in three female carriers among the members of the presented family. (PMID:21717404)
• The results of this study proposed that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions (PMID:22016523)
• Peculiar prolactinomas in patients with pituitary developmental Kal 2 gene mutations (PMID:22801565)
• we demonstrate that missense mutations reported in patients with KS, C172R and N267K did not alter or substantially reduce, respectively, the binding to FGFR1 (PMID:23189990)
• Increased presence of anosmin-1 in TGF-beta treated human retinal pigment epithelial cells cells, with distinct localization at the intercellular junctions. (PMID:23357298)
• Mutation analysis reveals a missense mutation of KAL1 in two brothers with Kallmann syndrome, while their mother is heterozygous for this missense mutation encoded by the single-nucleotide polymorphism rs2229013. (PMID:23410897)
• genetic association studies in population in Massachusetts: Data suggest that clinical features in Kallmann syndrome (KS) are highly associated with genetic causes: synkinesia is associated with genetic variations/mutations in KAL1. (PMID:23533228)
• These results indicate that intragenic multiexon deletions are one of the most frequent KAL1 abnormalities, which can be more accurately detected by multiplex ligation-dependent probe amplification. (PMID:23721716)
• No abnormalities were found in the patient group for the PROKR2 and GNRH1genes. In addition, no genomic rearrangements were identified in the healthy control individuals for the described genes (PMID:24002956)
• Anosmin-1 can facilitate tumor cell proliferation, migration, invasin, and survival. (PMID:24189182)
• Two brothers presented with a sensorineural hearing impairment associated with cryptorchidism and abnormal movements. Genome-wide array analysis identified a large deletion of KAL1 in both patients confirming the diagnosis of Kallmann syndrome. (PMID:24232061)
• Mutations were found in the following genes in one or more patients with congenital hypogonadotropic hypogonadism: KAL1, FGFR1, GNRHR, and CHD7 (PMID:24732674)
• data indicated KAL1 plays potential suppressive role on OSCC initiation and progression. KAL1 gene may serve as adjuvant biomarker for identification of pathological grade. (PMID:25060050)
• anosmin-1 has been identified in other pathological scenarios both within (multiple sclerosis) and outside (cancer, atopic dermatitis) the central nerve system. (PMID:25300141)
• FGF receptor 1-mediated anosmin-1 activity plays a crucial role in the continuous remodelling of the adult olfactory bulb. (PMID:25300351)
• Anosmin-1 over-expression regulates oligodendrocyte precursor cell proliferation, migration and myelin sheath thickness. Data confirmed the involvement of (A1) works as a chemotropic cue contributing to axonal outgrowth and in oligodendrogliogenesis and its relevance for myelination. (PMID:25662897)
• Our analyses show that the two phenotypes in our patient are due to independent genetic defects: a genomic rearrangement involving the KAL1 gene and a point mutation of the steryl-sulfatase gene. (PMID:25726327)
• Results indicated that KAL1 may act as a putative tumor suppressor in hepatocellular carcinoma (HCC) and is inactivated by promoter hypermethylation. KAL1 may serve as a biomarker of malignant phenotype of HCC. (PMID:25892360)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	anos1a	ENSDARG00000012896
danio_rerio	ANOS1	ENSDARG00000112637
drosophila_melanogaster	Kal1	FBGN0039155
caenorhabditis_elegans	kal-1	WBGENE00002181

Protein

Protein identifiers

Anosmin-1 — P23352 (reviewed: P23352)

Alternative names: Adhesion molecule-like X-linked, Kallmann syndrome protein

All UniProt accessions (1): P23352

UniProt curated annotations — full annotation on UniProt →

Function. Has a dual branch-promoting and guidance activity, which may play an important role in the patterning of mitral and tufted cell collaterals to the olfactory cortex. Chemoattractant for fetal olfactory epithelial cells.

Subunit / interactions. Interacts with FGFR1; this interaction does not interfere with FGF2-binding to FGFR1. Binds heparin. Heparin may promote or interfere with ANOS1-FGFR1-FGF2 complex formation depending on the sequential order of its binding to the various constituents. For instance, heparin-ANOS1 interaction favors subsequent binding to pre-existing binary FGFR1-FGF2 complex, while heparin-FGF2 complex does not interact with ANOS1-FGFR1.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Expressed in the cerebellum (at protein level).

Post-translational modifications. N-glycosylated. May be proteolytically cleaved at the cell surface and released from the cell surface.

Disease relevance. Hypogonadotropic hypogonadism 1 with or without anosmia (HH1) [MIM:308700] 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. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in ANOS1 as well as in other HH-associated genes including FGFR1 and TACR3.

RefSeq proteins (1): NP_000207* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR008197	WAP_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036645	Elafin-like_sf	Homologous_superfamily
IPR040957	Anosmin-1_Cys_box	Domain
IPR042447	Anosmin-1	Family

Pfam: PF00041, PF00095, PF17869

UniProt features (43 total): sequence variant 19, glycosylation site 6, disulfide bond 5, domain 5, sequence conflict 4, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1ZLG	SOLUTION SCATTERING

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23352-F1	76.88	0.34

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 (5): 49–83, 53–77, 86–105, 90–101, 116–120

Glycosylation sites (6): 209, 300, 470, 553, 564, 71

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-190373	FGFR1c ligand binding and activation
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-162582	Signal Transduction
R-HSA-190236	Signaling by FGFR
R-HSA-190242	FGFR1 ligand binding and activation
R-HSA-5654736	Signaling by FGFR1
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 266 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, SHEPARD_BMYB_MORPHOLINO_DN, MODULE_66, GOBP_TAXIS, WOO_LIVER_CANCER_RECURRENCE_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, ONDER_CDH1_TARGETS_2_UP, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (4): chemotaxis (GO:0006935), cell adhesion (GO:0007155), axon guidance (GO:0007411), neuron differentiation (GO:0030182)

GO Molecular Function (5): serine-type endopeptidase inhibitor activity (GO:0004867), extracellular matrix structural constituent (GO:0005201), heparin binding (GO:0008201), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), extracellular matrix (GO:0031012), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by FGFR1	2
FGFR1 ligand binding and activation	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by FGFR	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to chemical	1
taxis	1
cellular process	1
axonogenesis	1
neuron projection guidance	1
cell differentiation	1
generation of neurons	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
structural molecule activity	1
extracellular matrix	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
membrane	1
cell periphery	1
external encapsulating structure	1

Protein interactions and networks

STRING

1002 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANOS1	PROKR2	Q8NFJ6	976
ANOS1	PROK2	Q9HC23	945
ANOS1	FGFR1	P11362	935
ANOS1	GNRH1	P01148	880
ANOS1	CHD7	Q9P2D1	836
ANOS1	FGF8	P55075	831
ANOS1	GNRHR	P30968	820
ANOS1	VCX3A	Q9NNX9	755
ANOS1	STS	P08842	746
ANOS1	HS6ST1	O60243	733
ANOS1	TACR3	P29371	718
ANOS1	NSMF	Q6X4W1	712
ANOS1	KISS1R	Q969F8	698
ANOS1	ARSL	P51690	698
ANOS1	TAC3	Q9UHF0	692
ANOS1	HPSE	Q9Y251	692

IntAct

28 interactions, top by confidence:

A	B	Type	Score
ANOS1	FGFR1	psi-mi:“MI:0407”(direct interaction)	0.630
FGFR1	ANOS1	psi-mi:“MI:0407”(direct interaction)	0.630
ANOS1	FGFR1	psi-mi:“MI:0403”(colocalization)	0.630
FGFR1	ANOS1	psi-mi:“MI:0403”(colocalization)	0.630
NCALD	ANOS1	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	ANOS1	psi-mi:“MI:0915”(physical association)	0.560
ANOS1	NCALD	psi-mi:“MI:0915”(physical association)	0.560
ANOS1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
	ANOS1	psi-mi:“MI:0407”(direct interaction)	0.540
CD44	PDPK1	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
ANOS1	KDR	psi-mi:“MI:0407”(direct interaction)	0.440
ANOS1	FGFR2	psi-mi:“MI:0407”(direct interaction)	0.440
ANOS1	FGF2	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
ANOS1	ZNF724	psi-mi:“MI:0914”(association)	0.350
MMTAG2	WDR46	psi-mi:“MI:0914”(association)	0.350
MECP2	ANOS1	psi-mi:“MI:0914”(association)	0.350
MRM1	ZNF316	psi-mi:“MI:0914”(association)	0.350
PIP4K2A	SAP18	psi-mi:“MI:0914”(association)	0.350
SDC1	TCAF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (152): KAL1 (Reconstituted Complex), KAL1 (Reconstituted Complex), KAL1 (Reconstituted Complex), KAL1 (Reconstituted Complex), FGFR1 (Reconstituted Complex), KAL1 (Reconstituted Complex), FN1 (Reconstituted Complex), Lama1 (Reconstituted Complex), Lamb1 (Reconstituted Complex), Lamb2 (Reconstituted Complex), FGFR1 (Affinity Capture-Western), KAL1 (Affinity Capture-RNA), NCALD (Two-hybrid), UBQLN1 (Two-hybrid), ZNF184 (Affinity Capture-MS)

ESM2 similar proteins: A0JPE1, A0JPH4, A2VDJ0, A4D0V7, A4IH36, A6H684, O75129, O88199, O95170, P16047, P23352, P33005, P97793, Q05004, Q08DV9, Q3U095, Q3U3D7, Q52KP5, Q5NDE4, Q5XI89, Q60943, Q68CR1, Q6L8S8, Q6L9W6, Q6PKC3, Q6Q2W4, Q6UWF7, Q7LFX5, Q7T2L7, Q7TN22, Q7Z443, Q80TS8, Q8CHI9, Q8JZL1, Q8K2W3, Q8N323, Q8N6G5, Q8NFM7, Q90369, Q91XQ5

Diamond homologs: A4K2M6, A4K2P0, A4K2P8, A4K2Q7, A4K2R5, A4K2S4, A4K2T3, A4K2U1, A4K2V4, A4K2W7, A4K2W8, A4K2X6, A4K2Y4, A7X4M7, P01173, P03973, P09837, P16225, P19957, P23352, P33005, Q29125, Q29126, Q6IE40, Q8WWY7, Q90369, Q9JHY3, A7X4I7, A7X4J4, A7X4K1, A7X4K7, A7X4L4, P00993, P01174, P60589, Q6NUX0, Q8CHN3, Q9DAU7, O46655, P09412

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NFIA	“down-regulates quantity”	ANOS1	“transcriptional regulation”
NFIB	“down-regulates quantity”	ANOS1	“transcriptional regulation”
NFIX	“down-regulates quantity”	ANOS1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ERK1 and ERK2 cascade	5	19.3×	4e-04
cell migration	5	14.0×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	30
Uncertain significance	215
Likely benign	63
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10002	NM_000216.4(ANOS1):c.1842+412_*1083del	Pathogenic
10003	NM_000216.4(ANOS1):c.711G>A (p.Trp237Ter)	Pathogenic
10004	NM_000216.4(ANOS1):c.769C>T (p.Arg257Ter)	Pathogenic
10005	NM_000216.4(ANOS1):c.774G>A (p.Trp258Ter)	Pathogenic
10006	NM_000216.4(ANOS1):c.831del (p.Ser278fs)	Pathogenic
10007	NG_007088.2:g.(37490_113516)_(149394_151790)del	Pathogenic
10008	NM_000216.4(ANOS1):c.1540G>A (p.Glu514Lys)	Pathogenic
10009	NM_000216.4(ANOS1):c.544_726+2del	Pathogenic
10010	NM_000216.4(ANOS1):c.95_105dup (p.Asp36fs)	Pathogenic
10011	NM_000216.4(ANOS1):c.784C>T (p.Arg262Ter)	Pathogenic
10012	NG_007088.2:g.(37490_113516)_(202869_204133)del	Pathogenic
10014	NG_007088.2:g.(37490_113516)_(151921_166482)del	Pathogenic
10015	NM_000216.4(ANOS1):c.1062+1G>T	Pathogenic
1027379	NM_000216.4(ANOS1):c.774del (p.Trp258fs)	Pathogenic
1069737	NM_000216.4(ANOS1):c.1890_1891delinsTT (p.Arg631Ter)	Pathogenic
1184534	NM_000216.4(ANOS1):c.67_92dup (p.Ala32fs)	Pathogenic
1351117	NM_000216.4(ANOS1):c.1766G>A (p.Trp589Ter)	Pathogenic
1356515	NM_000216.4(ANOS1):c.1756C>T (p.Gln586Ter)	Pathogenic
1387367	NM_000216.4(ANOS1):c.171_181del (p.Gln57fs)	Pathogenic
1390065	NC_000023.10:g.(?8501036)(8591731_?)del	Pathogenic
140614	NM_000216.4(ANOS1):c.1A>G (p.Met1Val)	Pathogenic
1408120	NM_000216.4(ANOS1):c.571C>T (p.Arg191Ter)	Pathogenic
1437964	NM_000216.4(ANOS1):c.586C>T (p.Gln196Ter)	Pathogenic
1439274	NM_000216.4(ANOS1):c.814C>T (p.Arg272Ter)	Pathogenic
1451691	NM_000216.4(ANOS1):c.203del (p.Phe68fs)	Pathogenic
1452668	NM_000216.4(ANOS1):c.1249C>T (p.Gln417Ter)	Pathogenic
1460215	NM_000216.4(ANOS1):c.1862dup (p.Pro622fs)	Pathogenic
146510	GRCh38/hg38 Xp22.31(chrX:7072209-9374317)x0	Pathogenic
1707443	GRCh37/hg19 Xp22.33-22.2(chrX:168546-11080743)x1	Pathogenic
1807764	GRCh37/hg19 Xp22.31(chrX:6658781-8760719)x1	Pathogenic

SpliceAI

3556 predictions. Top by Δscore:

Variant	Effect	Δscore
X:8534317:A:AC	donor_gain	1.0000
X:8534318:C:CG	donor_gain	1.0000
X:8534318:CT:C	donor_gain	1.0000
X:8534318:CTGT:C	donor_gain	1.0000
X:8534456:TGATC:T	acceptor_gain	1.0000
X:8534459:TC:T	acceptor_gain	1.0000
X:8534460:CC:C	acceptor_gain	1.0000
X:8534461:C:CA	acceptor_loss	1.0000
X:8534461:C:CC	acceptor_gain	1.0000
X:8534462:T:C	acceptor_loss	1.0000
X:8535589:A:AC	donor_gain	1.0000
X:8535590:C:CC	donor_gain	1.0000
X:8535676:TGAA:T	donor_gain	1.0000
X:8536902:T:C	acceptor_gain	1.0000
X:8554099:C:CC	acceptor_gain	1.0000
X:8568230:A:AC	donor_gain	1.0000
X:8568231:C:CA	donor_gain	1.0000
X:8568231:CT:C	donor_gain	1.0000
X:8568231:CTG:C	donor_gain	1.0000
X:8568231:CTGT:C	donor_gain	1.0000
X:8568231:CTGTT:C	donor_gain	1.0000
X:8568372:TGAAA:T	acceptor_gain	1.0000
X:8568373:GAAA:G	acceptor_gain	1.0000
X:8568375:AA:A	acceptor_gain	1.0000
X:8568375:AAC:A	acceptor_loss	1.0000
X:8568376:ACTA:A	acceptor_loss	1.0000
X:8568377:C:CC	acceptor_gain	1.0000
X:8585262:CTGA:C	donor_loss	1.0000
X:8585263:TGACC:T	donor_loss	1.0000
X:8585264:GACC:G	donor_loss	1.0000

AlphaMissense

4416 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:8587809:C:A	W237C	1.000
X:8587809:C:G	W237C	1.000
X:8587910:A:G	W204R	1.000
X:8587910:A:T	W204R	1.000
X:8597123:C:T	C151Y	1.000
X:8597146:A:C	F143L	1.000
X:8597146:A:T	F143L	1.000
X:8597147:A:C	F143C	1.000
X:8597148:A:G	F143L	1.000
X:8535722:A:G	W571R	0.999
X:8535722:A:T	W571R	0.999
X:8585289:G:C	S278R	0.999
X:8585289:G:T	S278R	0.999
X:8585291:T:G	S278R	0.999
X:8585314:C:T	G270E	0.999
X:8585322:A:C	N267K	0.999
X:8585322:A:T	N267K	0.999
X:8585333:C:G	A264P	0.999
X:8585338:C:G	R262P	0.999
X:8587811:A:G	W237R	0.999
X:8587811:A:T	W237R	0.999
X:8597060:C:G	C172S	0.999
X:8597060:C:T	C172Y	0.999
X:8597061:A:G	C172R	0.999
X:8597061:A:T	C172S	0.999
X:8597083:A:C	C164W	0.999
X:8597085:A:G	C164R	0.999
X:8597086:A:C	C163W	0.999
X:8597087:C:G	C163S	0.999
X:8597088:A:G	C163R	0.999

dbSNP variants (sampled 300 via entrez): RS1000008900 (X:8674787 A>G), RS1000011339 (X:8685659 A>G), RS1000063777 (X:8551199 G>A), RS1000065355 (X:8704966 G>C), RS1000069113 (X:8538485 C>T), RS1000074088 (X:8675569 T>C), RS1000096550 (X:8678168 T>C), RS1000097661 (X:8619747 A>G), RS1000110136 (X:8562051 G>A,C), RS1000121027 (X:8539558 A>G), RS1000130599 (X:8548759 G>C), RS1000148735 (X:8638494 T>C), RS1000149161 (X:8712414 A>G), RS1000159885 (X:8619751 T>G), RS1000170583 (X:8677603 A>G,T)

Disease associations

OMIM: gene MIM:300836 | disease phenotypes: MIM:308700, MIM:146110, MIM:147950, MIM:212720

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 1 with or without anosmia	Definitive	X-linked
Kallmann syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 1 with or without anosmia	Definitive	XL

Mondo (6): hypogonadotropic hypogonadism 1 with or without anosmia (MONDO:0010635), amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), hypogonadotropic hypogonadism (MONDO:0018555), Martsolf syndrome 1 (MONDO:8000008), Kallmann syndrome (MONDO:0018800)

Orphanet (3): Kallmann syndrome (Orphanet:478), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000029	Testicular atrophy
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000122	Unilateral renal agenesis
HP:0000144	Decreased fertility
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000324	Facial asymmetry
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:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001288	Gait disturbance

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007876_10	Estimated glomerular filtration rate	1.000000e-08

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
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
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)
C536028	Martsolf syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs137852517	ANOS1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	4
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
trichostatin A	decreases expression, affects cotreatment	2
Decitabine	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
terbufos	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
Vorinostat	affects cotreatment, decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases expression	1
Calcitriol	increases expression	1
Cisplatin	affects expression	1
Fonofos	increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	decreases expression	1
Parathion	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Progesterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Cyclosporine	decreases expression	1
Palmitic Acid	increases expression	1
Okadaic Acid	increases expression	1
Heparan Sulfate Proteoglycans	affects binding	1

Clinical trials (associated diseases)

116 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
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
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
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism