KLB

Summary

KLB (klotho beta, HGNC:15527) is a protein-coding gene on chromosome 4p14, encoding Beta-klotho (Q86Z14). Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.

Enables fibroblast growth factor binding activity and fibroblast growth factor receptor binding activity. Predicted to be involved in carbohydrate metabolic process. Predicted to act upstream of or within positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway and positive regulation of cell population proliferation. Predicted to be located in plasma membrane.

Source: NCBI Gene 152831 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism (Strong, GenCC)
• GWAS associations: 28
• Clinical variants (ClinVar): 249 total — 1 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_175737

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15527
Approved symbol	KLB
Name	klotho beta
Location	4p14
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134962
Ensembl biotype	protein_coding
OMIM	611135
Entrez	152831

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000257408, ENST00000859482

RefSeq mRNA: 1 — MANE Select: NM_175737 NM_175737

CCDS: CCDS3451

Canonical transcript exons

ENST00000257408 — 5 exons

Exon	Start	End
ENSE00001077287	39434210	39434720
ENSE00001123064	39406930	39407774
ENSE00001171001	39446332	39447475
ENSE00001171008	39437727	39437995
ENSE00001236571	39448301	39451533

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 89.32.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4540 / max 181.6200, expressed in 222 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47370	0.7228	105
47368	0.2898	42
47375	0.0912	45
47369	0.0898	32
47372	0.0891	27
47373	0.0842	42
47374	0.0534	29
47371	0.0336	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	89.32	gold quality
buccal mucosa cell	CL:0002336	88.00	gold quality
liver	UBERON:0002107	84.23	gold quality
right lobe of liver	UBERON:0001114	79.88	gold quality
ileal mucosa	UBERON:0000331	78.68	gold quality
adipose tissue	UBERON:0001013	78.40	gold quality
subcutaneous adipose tissue	UBERON:0002190	75.97	gold quality
adult organism	UBERON:0007023	75.17	gold quality
skin of hip	UBERON:0001554	74.20	gold quality
esophagus squamous epithelium	UBERON:0006920	73.13	silver quality
thoracic mammary gland	UBERON:0005200	72.38	gold quality
mammary gland	UBERON:0001911	72.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.99	gold quality
pancreatic ductal cell	CL:0002079	70.34	silver quality
adipose tissue of abdominal region	UBERON:0007808	69.88	gold quality
mammary duct	UBERON:0001765	69.03	gold quality
synovial joint	UBERON:0002217	68.96	gold quality
epithelium of mammary gland	UBERON:0003244	68.94	gold quality
omental fat pad	UBERON:0010414	68.44	gold quality
peritoneum	UBERON:0002358	68.36	gold quality
tibialis anterior	UBERON:0001385	68.17	silver quality
body of pancreas	UBERON:0001150	67.83	gold quality
pancreas	UBERON:0001264	66.74	gold quality
gingival epithelium	UBERON:0001949	66.41	silver quality
upper leg skin	UBERON:0004262	66.19	gold quality
islet of Langerhans	UBERON:0000006	65.50	gold quality
parietal pleura	UBERON:0002400	65.15	gold quality
gingiva	UBERON:0001828	64.06	gold quality
mucosa of sigmoid colon	UBERON:0004993	63.71	gold quality
colonic mucosa	UBERON:0000317	63.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting KLB, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6885-3P	99.75	70.36	3187

Literature-anchored findings (GeneRIF, showing 40)

• The down-regulation of the renal klotho gene could increase renal damage induced by angiotensin II, while klotho gene induction could have therapeutic possibilities in treating angiotensin II-induced kidney damage. (PMID:16358222)
• Liver-specific activities of FGF19 require Klotho beta. (PMID:17627937)
• a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho (PMID:17711860)
• High expression of Klotho is associated with ovarian disease progression (PMID:18259951)
• Both FGF23 and FGF21 require intact alpha or betaKlotho for signaling, respectively, whereas FGF19 can signal through a Klotho chimera consisting of the N terminus of alphaKlotho and the C terminus of betaKlotho. (PMID:18829467)
• These data demonstrate that the C-terminus of FGF21 is critical for binding to beta-Klotho and the N-terminus is critical for fibroblast growth factor receptor (FGFR) activation. (PMID:19059246)
• Metabolic regulator betaKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation. (PMID:20657013)
• A functional KLB gene variant mediating protein stability associates with colonic transit in irritable bowel syndrome with diarrhea. This association is modulated by 2 genetic variants in FGFR4. (PMID:21396369)
• Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho. (PMID:21653700)
• Data suggest that KLB is an important regulator in the immortalization of HCECs by facilitating FGF19 growth factor signaling. (PMID:22020932)
• Deletion of the D1 and the D1-D2 linker (the D1/linker region) from FGFR1c led to beta-Klotho-independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region-deficient FGFR1c. (PMID:22248288)
• Polymorphism KLB rs4975017 may influence the colonic transit response to colesevelam in female patients with irritable bowel syndrome with diarrhea. (PMID:22271411)
• KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. (PMID:22439738)
• Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. (PMID:22442730)
• KLB and FGFR1 form a 1:1 heterocomplex independent of the galectin lattice that transitions to a 1:2 complex upon the addition of FGF21. (PMID:22523080)
• betaKlotho suppresses tumor growth in hepatocellular carcinoma by regulating Akt/GSK-3beta/cyclin D1 signaling pathway. (PMID:23383245)
• In-depth DNA sequencing identified additional genetic coding and noncoding variants in KLB that are associated with fecal bile acids excretion or colonic transit in Irritable bowel syndrome-diarrhea. (PMID:24200957)
• obesity appears as the predominant determinant of the abnormalities in FGF21 and FGF19 levels. Opposite changes in beta-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity (PMID:24813368)
• Variants in genes involved in feedback regulation of bile acid synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the irritable bowel syndrome-diarrhea subgroup with elevated serum C4. (PMID:25070056)
• ATF4 signaling pathway is essential for mediating the effect of ER stress on beta-klotho expression. (PMID:25727012)
• A high expression level of KLbeta, but not KLalpha, was an independent predictive factor of short progression free survival for non-muscle invasive bladder cancer (PMID:27573985)
• Our results suggest that KLbeta plays important roles in tumor invasion and progression, and its concentration may be a valuable urinebased marker for the detection of bladder cancer. (PMID:27573985)
• We conducted a genome-wide association meta-analysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). (PMID:27911795)
• the metabolic FGF21/KLB/FGFR1 pathway is involved in congenital hypogonadotropic hypogonadism (CHH) Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. (PMID:28754744)
• crystal structures of free and ligand-bound beta-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards beta-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner (PMID:29342135)
• a disrupted FGF19/FGFR4/betaKL signaling pathway may play a role in the development of thyroid cancers. (PMID:29438906)
• Knockdown of beta-Klotho produced the opposite effects. In conclusion, beta-Klotho inhibits EMT and plays a tumorsuppressive role in prostate cancer (PCa) , linking FGF/FGFR/beta-Klotho signaling to the regulation of PCa progression. (PMID:29749458)
• Study demonstrated, for the first time, that betaKlotho was strongly expressed in cells infiltrating the lesional dermis of psoriatic patients compared with control or atopic dermatitis patients and in cells infiltrating the skin of imiquimod-treated mice than in untreated mice. (PMID:30302794)
• mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein (PMID:30317562)
• The betaKlotho gene expression might be involved in endometrioid endometrial cancer tumorgenesis. The betaKlotho may in future be used as an useful indicator for endometrial cancer, although further studies are needed (PMID:30393845)
• Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma. (PMID:30698907)
• Studied binding interactions and molecular structure of fibroblast growth factor 19 and beta-Klotho. (PMID:30944224)
• The interplay of Klotho with signaling pathway and microRNAs in cancers. (PMID:31127658)
• Our results indicate that a disrupted signaling pathway for betaKL, FGFR4 and IGF-1R may play a role in the development of medullary thyroid cancers. (PMID:31184820)
• KLB gene polymorphism is associated with obesity and non-alcoholic fatty liver disease in the Han Chinese. (PMID:31548436)
• Dual labeling of cell-type markers vs. RBM3/beta-klotho revealed enriched staining of targets in neurons in the developing brain. Identifying that RBM3/beta-klotho is abundant in neurons in the immature brain is fundamentally important to guide protocol design and conceptual frameworks germane to future testing of these neuroprotective pathways in humans. (PMID:31566073)
• beta-Klotho gene variation is associated with liver damage in children with NAFLD. (PMID:31655133)
• Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications. (PMID:31792355)
• Serum beta-Klotho concentrations are increased in women with polycystic ovary syndrome. (PMID:32673996)
• The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation. (PMID:33640795)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	klb	ENSDARG00000076294
mus_musculus	Klb	ENSMUSG00000029195
rattus_norvegicus	Klb	ENSRNOG00000002834
drosophila_melanogaster	CG9701	FBGN0036659
caenorhabditis_elegans		WBGENE00016848
caenorhabditis_elegans		WBGENE00017103

Paralogs (4): LCT (ENSG00000115850), KL (ENSG00000133116), LCTL (ENSG00000188501), GBA3 (ENSG00000249948)

Protein

Protein identifiers

Beta-klotho — Q86Z14 (reviewed: Q86Z14)

Alternative names: Klotho beta-like protein

All UniProt accessions (1): Q86Z14

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21.

Subunit / interactions. Interacts with FGFR1 and FGFR4. Interacts with FGF19; this interaction is direct. Interacts (via C-terminus) with FGF21; this interaction is direct.

Subcellular location. Cell membrane.

Domain organisation. Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 241, and the second one lacks the essential Glu active site residue at position 889. These domains are therefore predicted to be inactive.

Similarity. Belongs to the glycosyl hydrolase 1 family. Klotho subfamily.

RefSeq proteins (1): NP_783864* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001360	Glyco_hydro_1	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily

Pfam: PF00232

UniProt features (101 total): helix 42, strand 32, glycosylation site 11, sequence variant 5, turn 5, topological domain 2, region of interest 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5VAK	X-RAY DIFFRACTION	1.7
5VAN	X-RAY DIFFRACTION	2.2
5VAQ	X-RAY DIFFRACTION	2.61
5WI9	X-RAY DIFFRACTION	2.7
6NFJ	X-RAY DIFFRACTION	3.19

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86Z14-F1	89.68	0.78

Antibody-complex structures (SAbDab): 5 — 5VAK, 5VAN, 5VAQ, 5WI9, 6NFJ

Functional residue map

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

Glycosylation sites (11): 308, 391, 554, 611, 702, 706, 971, 71, 120, 125, 211

Function

Pathways and Gene Ontology

Reactome pathways

30 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1307965	betaKlotho-mediated ligand binding
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-112399	IRS-mediated signalling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-190236	Signaling by FGFR
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-2404192	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
R-HSA-2428924	IGF1R signaling cascade
R-HSA-2428928	IRS-related events triggered by IGF1R
R-HSA-5654716	Downstream signaling of activated FGFR4
R-HSA-5654743	Signaling by FGFR4
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-74751	Insulin receptor signalling cascade
R-HSA-74752	Signaling by Insulin receptor
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 106 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, REACTOME_SIGNALING_BY_FGFR, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, HNF1_Q6, PATIL_LIVER_CANCER, MARTINEZ_RB1_TARGETS_UP, GOBP_RESPONSE_TO_FIBROBLAST_GROWTH_FACTOR, GATA6_01, INGRAM_SHH_TARGETS_UP, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, RYTAAWNNNTGAY_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_RESPONSE_TO_GROWTH_FACTOR, HNF1_C, GOBP_FIBROBLAST_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (4): carbohydrate metabolic process (GO:0005975), positive regulation of cell population proliferation (GO:0008284), positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway (GO:0090080), fibroblast growth factor receptor signaling pathway (GO:0008543)

GO Molecular Function (4): hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), fibroblast growth factor receptor binding (GO:0005104), fibroblast growth factor binding (GO:0017134), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Downstream signaling of activated FGFR4	4
Signaling by FGFR4	2
Signaling by Receptor Tyrosine Kinases	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR4 ligand binding and activation	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
IRS-related events triggered by IGF1R	1
Insulin receptor signalling cascade	1
PIP3 activates AKT signaling	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
MAPK cascade	1
fibroblast growth factor receptor signaling pathway	1
positive regulation of MAPK cascade	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
hydrolase activity, acting on glycosyl bonds	1
growth factor receptor binding	1
growth factor binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1115 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLB	FGFR4	P22455	999
KLB	FGF21	Q9NSA1	999
KLB	FGF19	O95750	998
KLB	FGFR1	P11362	997
KLB	FGF23	Q9GZV9	966
KLB	FGF4	P08620	922
KLB	FGFR2	P18443	856
KLB	FGF18	O76093	855
KLB	FGF20	Q9NP95	848
KLB	FGF16	O43320	848
KLB	FGF9	P31371	848
KLB	FGF22	Q9HCT0	847
KLB	FGF10	O15520	845
KLB	FGF7	P21781	845
KLB	FGF6	P10767	844
KLB	FGF17	O60258	844

IntAct

12 interactions, top by confidence:

A	B	Type	Score
KLB	FGF21	psi-mi:“MI:0407”(direct interaction)	0.440
KLB	FGFR1	psi-mi:“MI:0407”(direct interaction)	0.440
KLB	CCT2	psi-mi:“MI:0915”(physical association)	0.400
KLB	PPIA	psi-mi:“MI:0915”(physical association)	0.400
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
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
	PSMD12	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): FGFR1 (Co-localization), KLB (FRET), KLB (Affinity Capture-Western), KLB (Affinity Capture-Western), KLB (Affinity Capture-Western), KLB (Affinity Capture-Western), KLB (Proximity Label-MS), KLB (Proximity Label-MS), KLB (Affinity Capture-MS), KLB (Affinity Capture-Western), KLB (Affinity Capture-MS), KLB (Affinity Capture-MS)

ESM2 similar proteins: B2GUY2, O18835, O35082, P04062, P17405, P17439, P18424, P22413, P57110, P58242, P82450, Q04519, Q0VD19, Q13219, Q2KHZ8, Q3MI05, Q566E5, Q5R8E3, Q5RFU0, Q5VSG8, Q6P1J0, Q6UWM7, Q6YGZ1, Q70KH2, Q71RP1, Q86Z14, Q8BYL4, Q8K1F9, Q8K3F2, Q8N119, Q8R2R1, Q8R4K8, Q8WP17, Q90YK5, Q92485, Q96JK4, Q99N32, Q9BDT0, Q9DGD1, Q9HAT2

Diamond homologs: A2SY66, A3BMZ5, A3C053, B3H5Q1, B6ZKM3, B6ZKM4, B6ZKM5, B6ZKN1, B7F7K7, B7F8N7, B8AVF0, B9FHH2, B9K7M5, E3W9M3, O35082, O64879, O64882, O64883, O65458, O80690, P09848, P09849, P10482, P26208, P29092, P37702, P97265, Q00326, Q02401, Q03506, Q08638, Q0DA21, Q0J0G1, Q0J0G2, Q0J0N4, Q1XH04, Q1XH05, Q1XIR9, Q25BW4, Q25BW5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	163
Likely benign	55
Benign	21

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2690953	NM_175737.4(KLB):c.2676del (p.Ile892fs)	Likely pathogenic

SpliceAI

917 predictions. Top by Δscore:

Variant	Effect	Δscore
4:39434208:A:AG	acceptor_gain	1.0000
4:39434209:G:GG	acceptor_gain	1.0000
4:39434721:G:C	donor_loss	1.0000
4:39437720:T:TA	acceptor_gain	1.0000
4:39437724:CA:C	acceptor_loss	1.0000
4:39437725:A:AC	acceptor_loss	1.0000
4:39437725:A:AG	acceptor_gain	1.0000
4:39437726:G:GG	acceptor_gain	1.0000
4:39437726:GC:G	acceptor_gain	1.0000
4:39437726:GCA:G	acceptor_gain	1.0000
4:39437726:GCAA:G	acceptor_gain	1.0000
4:39437726:GCAAT:G	acceptor_gain	1.0000
4:39437993:AAGGT:A	donor_loss	1.0000
4:39437994:AGGTA:A	donor_loss	1.0000
4:39437995:GGTA:G	donor_loss	1.0000
4:39437996:GTAA:G	donor_loss	1.0000
4:39447435:G:GT	donor_gain	1.0000
4:39447450:G:T	donor_gain	1.0000
4:39431242:A:T	donor_gain	0.9900
4:39432575:C:G	acceptor_gain	0.9900
4:39434204:TTTTA:T	acceptor_loss	0.9900
4:39434206:TTA:T	acceptor_loss	0.9900
4:39434208:AGGCT:A	acceptor_loss	0.9900
4:39434209:G:A	acceptor_loss	0.9900
4:39436349:C:G	donor_gain	0.9900
4:39437722:T:TA	acceptor_gain	0.9900
4:39437722:TGCAG:T	acceptor_gain	0.9900
4:39437724:CAGCA:C	acceptor_gain	0.9900
4:39437725:AGCAA:A	acceptor_gain	0.9900
4:39437996:G:GG	donor_gain	0.9900

AlphaMissense

6871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:39446788:T:A	W688R	0.995
4:39446788:T:C	W688R	0.995
4:39407574:T:A	W209R	0.994
4:39407574:T:C	W209R	0.994
4:39446535:G:C	W603C	0.994
4:39446535:G:T	W603C	0.994
4:39446709:G:C	W661C	0.994
4:39446709:G:T	W661C	0.994
4:39446533:T:A	W603R	0.993
4:39446533:T:C	W603R	0.993
4:39446707:T:A	W661R	0.993
4:39446707:T:C	W661R	0.993
4:39446735:T:C	F670S	0.993
4:39407412:T:A	W155R	0.991
4:39407412:T:C	W155R	0.991
4:39446790:G:C	W688C	0.991
4:39446790:G:T	W688C	0.991
4:39446807:C:A	P694H	0.991
4:39434669:G:C	D429H	0.990
4:39446735:T:G	F670C	0.990
4:39434583:T:C	L400P	0.989
4:39434720:G:C	A446P	0.989
4:39446804:A:T	E693V	0.989
4:39434294:T:A	W304R	0.988
4:39434294:T:C	W304R	0.988
4:39434639:T:A	W419R	0.988
4:39434639:T:C	W419R	0.988
4:39437869:G:C	K493N	0.987
4:39437869:G:T	K493N	0.987
4:39437969:T:A	W527R	0.987

dbSNP variants (sampled 300 via entrez): RS1000000284 (4:39416626 GA>G), RS1000144456 (4:39409085 C>T), RS1000175323 (4:39409455 T>C), RS1000199798 (4:39413729 A>G), RS10003153 (4:39436869 C>A), RS1000320636 (4:39450095 G>C), RS10003369 (4:39406975 C>A), RS1000372580 (4:39416371 T>C), RS1000483451 (4:39441341 T>C), RS1000542106 (4:39433628 G>A), RS1000575492 (4:39420649 C>T), RS1000607387 (4:39415348 G>A), RS10006966 (4:39429650 A>C), RS1000730209 (4:39451884 G>A,C), RS1000740848 (4:39426748 C>T)

Disease associations

OMIM: gene MIM:611135 | disease phenotypes: MIM:614462, MIM:212720, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism	Strong	Autosomal dominant

Mondo (5): amenorrhea (MONDO:0001836), lipoic acid synthetase deficiency (MONDO:0013762), Martsolf syndrome 1 (MONDO:8000008), ocular motility disease (MONDO:0001584), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (4): Lipoic acid synthetase deficiency (Orphanet:401859), Cataract-intellectual disability-hypogonadism syndrome (Orphanet:1387), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000141	Amenorrhea
HP:0000044	Hypogonadotropic hypogonadism

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST004026_3	Alcohol consumption	9.000000e-12
GCST004405_3	Alcohol consumption (drinks per week)	9.000000e-08
GCST004405_4	Alcohol consumption (drinks per week)	9.000000e-11
GCST004405_8	Alcohol consumption (drinks per week)	1.000000e-07
GCST004886_16	Alcohol consumption	8.000000e-19
GCST004886_3	Alcohol consumption	7.000000e-11
GCST004886_9	Alcohol consumption	9.000000e-10
GCST004887_3	Alcohol consumption in current drinkers	6.000000e-18
GCST006716_4	Alcohol use disorder (total score)	7.000000e-21
GCST006716_5	Alcohol use disorder (total score)	3.000000e-09
GCST006717_5	Alcohol use disorder (dependence and problematic use scores)	1.000000e-09
GCST006718_2	Alcohol use disorder (consumption score)	5.000000e-17
GCST007269_36	Pulse pressure	3.000000e-09
GCST007328_2	Alcohol consumption (drinks per week)	3.000000e-41
GCST007328_69	Alcohol consumption (drinks per week)	4.000000e-09
GCST007798_64	Asthma	3.000000e-07
GCST007799_16	Asthma (adult onset)	1.000000e-06
GCST008062_84	Blood urea nitrogen levels	3.000000e-12
GCST008258_10	Alcohol use disorder (consumption score)	3.000000e-09
GCST008258_29	Alcohol use disorder (consumption score)	3.000000e-09
GCST008522_28	Bitter alcoholic beverage consumption	4.000000e-33
GCST008757_43	Alcohol consumption	3.000000e-68
GCST008811_25	Alcohol consumption (drinks per week)	2.000000e-42
GCST008972_221	Urate levels	2.000000e-08
GCST009797_2	Alcohol consumption (heavy vs. light/non-drinkers)	6.000000e-16
GCST009800_3	Alcohol consumption (drinks per week)	4.000000e-06
GCST010546_10	Problematic alcohol use	5.000000e-19
GCST012336_5	Alcohol use disorder (consumption score)	1.000000e-19

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0009458	alcohol use disorder measurement
EFO:0007835	alcohol dependence measurement
EFO:0005763	pulse pressure measurement
EFO:1002011	adult onset asthma
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
C536028	Martsolf syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4630720 (PROTEIN COMPLEX), CHEMBL4804255 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11940694	Dosage	3	ethanol	Alcohol abuse

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11940694	KLB	3	0.00	1	ethanol

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
Valproic Acid	increases expression, increases methylation, affects expression	3
Aflatoxin B1	decreases expression, decreases methylation	3
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	decreases expression	1
cylindrospermopsin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol S	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Silicon Dioxide	decreases expression	1
Silver	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	1
Okadaic Acid	increases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
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
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism