KL

Summary

KL (klotho, HGNC:6344) is a protein-coding gene on chromosome 13q13.1, encoding Klotho (Q9UEF7). May have weak glycosidase activity towards glucuronylated steroids.

This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss.

Source: NCBI Gene 9365 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tumoral calcinosis, hyperphosphatemic, familial, 1 (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 579 total
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_004795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6344
Approved symbol	KL
Name	klotho
Location	13q13.1
Locus type	gene with protein product
Status	Approved
Aliases	KLA
Ensembl gene	ENSG00000133116
Ensembl biotype	protein_coding
OMIM	604824
Entrez	9365

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000380099, ENST00000487852

RefSeq mRNA: 1 — MANE Select: NM_004795 NM_004795

CCDS: CCDS9347

Canonical transcript exons

ENST00000380099 — 5 exons

Exon	Start	End
ENSE00000907334	33055047	33055315
ENSE00001483718	33063849	33066143
ENSE00003513781	33016423	33017259
ENSE00003595954	33060679	33061780
ENSE00003661181	33053767	33054277

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 97.96.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9898 / max 361.4758, expressed in 161 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134715	0.9898	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	97.96	gold quality
nephron tubule	UBERON:0001231	97.48	gold quality
kidney epithelium	UBERON:0004819	95.60	gold quality
adult organism	UBERON:0007023	94.15	gold quality
renal medulla	UBERON:0000362	94.14	gold quality
renal glomerulus	UBERON:0000074	93.16	gold quality
metanephric glomerulus	UBERON:0004736	92.70	gold quality
adult mammalian kidney	UBERON:0000082	91.40	gold quality
kidney	UBERON:0002113	90.08	gold quality
cortex of kidney	UBERON:0001225	85.61	gold quality
corpus epididymis	UBERON:0004359	84.56	gold quality
placenta	UBERON:0001987	84.28	gold quality
metanephros	UBERON:0000081	83.28	gold quality
CA1 field of hippocampus	UBERON:0003881	83.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.12	gold quality
pigmented layer of retina	UBERON:0001782	78.69	gold quality
islet of Langerhans	UBERON:0000006	77.29	gold quality
lower lobe of lung	UBERON:0008949	76.54	gold quality
caput epididymis	UBERON:0004358	76.06	gold quality
right lung	UBERON:0002167	74.62	gold quality
metanephros cortex	UBERON:0010533	72.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.78	gold quality
lung	UBERON:0002048	71.38	gold quality
upper lobe of lung	UBERON:0008948	71.10	gold quality
upper lobe of left lung	UBERON:0008952	70.90	gold quality
adipose tissue	UBERON:0001013	69.77	gold quality
jejunal mucosa	UBERON:0000399	69.74	gold quality
prostate gland	UBERON:0002367	69.21	gold quality
omental fat pad	UBERON:0010414	68.64	gold quality
connective tissue	UBERON:0002384	68.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	40.74
E-ANND-3	yes	5.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, HMGA1, HNRNPK, NR5A2, PPARG, SP1, TBX15, TCF3, VDR, ZFPM2

miRNA regulators (miRDB)

130 targeting KL, 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-656-3P	100.00	72.15	2788
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Association of human aging with a functional variant of klotho. (PMID:11792841)
• Klotho gene polymorphism is associated with bone density and spondylosis of the lumbar spine in Japanese postmenopausal women. (PMID:12110410)
• Klotho polymorphisms & bone density in white and the Japanese postmenopausal women found 11 polymorphisms;3 were common in both populations. Klotho may be involved in the pathophysiology of bone loss with aging in humans. (PMID:12369777)
• Expression of klotho RNA was greatly reduced in kidneys of all chronic renal failure patients. Dietary P(i) restriction induced klotho expression, which enhances beneficial effect of P(i) restriction in patients with CRF and/or on haemodialysis. Review. (PMID:12771308)
• Cross-sectional and prospective studies confirm a genetic model in which the KL-VS allele confers a heterozygous advantage in conjunction with a marked homozygous disadvantage for HDL-C levels, systolic blood pressure, stroke, and longevity. (PMID:15677572)
• several single nucleotide polymorphisms in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis (PMID:15784727)
• The Klotho gene has been identified as one of the genes that may regulate cirulating osteocalcin levels. (PMID:16151675)
• Our study suggests that Klotho acts as a humoral factor to reduce H(2)O(2)-induced apoptosis and cellular senescence in vascular cells. (PMID:16325773)
• No evidence that the single nucleotide polymorphism F352V that defines the KL-VS variant of KLOTHO is involved in the genetic susceptibility to type 2 diabetes in a large case-control and family-based study. (PMID:16753056)
• the F352V Klotho polymorphism is associated with bone mineral density in postmenopausal women, suggesting that Klotho gene variants influence skeletal aging (PMID:16955217)
• KLOTHO G395A polymorphism was associated with blood pressure and KLOTHO C1818T polymorphism was associated with glucose metabolism (PMID:16957409)
• the KLOTHO gene is a candidate gene of atherosclerosis in humans (PMID:16979405)
• Klotho normally regulates cellular senescence by repressing the p53/cyclin-dependent kinase inhibitor 1A pathway (PMID:17014852)
• common mechanism of KLOTHO down-regulation, but executed at various times in life, may underlie both physiological and disease-related T cell aging (PMID:17202338)
• allelic variants of Klotho constitute one of the genetic factors influencing bone mineral density in male adults. (PMID:17205327)
• one variant in KLOTHO gene is associated with the susceptibility of hand osteoarthritis and appears to act through osteophyte formation rather than cartilage damage (PMID:17270470)
• key factor regulating mineral and vitamin D metabolism (PMID:17332731)
• Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of fibroblast growth factor 19, -21, and -23 to their cognate receptors (PMID:17339340)
• failure to find any significant association between leukocyte telomere length and 10 single nucleotide polymorphisms in two ageing-related candidate genes, TGFB1 and KLOTHO (PMID:17624411)
• believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans (PMID:17710231)
• a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho (PMID:17711860)
• elevated alpha-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate alpha-Klotho in the selective regulation of phosphate levels and in the regulation of parathyroid mass and function (PMID:18308935)
• An association was observed between SNPs G395A and C2998T of the KLOTHO gene and knee osteoarthritis. (PMID:18465812)
• a noncanonical PPAR-responsive element within the 5’-flanking region of the human klotho gene (PMID:18547997)
• might play pivotal roles in minerametabolism as regulators that integrate calcium and phosphate homeostasis. (review) (PMID:18591743)
• This review summarizes recent progress in understanding of Klotho function in the regulation of tissue-specific metabolic activity of the endocrine fibroblast growth factors–REVIEW (PMID:18660672)
• These data provide new insights into the physiological roles of FGF-23 and Klotho. (PMID:18678710)
• Type I membrane klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism. (PMID:18682507)
• review of expression and functions of klotho and the upregulation of klotho by PPARG (PMID:18756295)
• klotho is a potential tumor suppressor and an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer (PMID:18762812)
• Klotho, a transmembrane protein, facilitates the interaction of FGF23 with its receptor. (PMID:19019915)
• klotho G-395A polymorphism could be a risk factor for early dysfunction of vascular access in HD patients (PMID:19119257)
• Klotho regulates urinary phosphate and calcium excretion and calcitriol synthesis, deglycosylates the calcium channel TRPV5 and regulates calcium-stimulated PTH secretion.[review] (PMID:19121771)
• Studies show that the transmembrane and secreted forms of Klotho protein have distinct functions, which may collectively affect aging processes. (PMID:19230844)
• KLOTHO gene G395A allele carrier state may be associated with CAD but not with coronary artery calcification in Korean population. (PMID:19246844)
• regulates clcium and phosphate metabolism. (review) (PMID:19329831)
• Klotho may have a broader function in the regulation of ion transport in the kidney. (PMID:19349416)
• Cordyceps sinensis extract can increase the expression of Kl down-regulated by Ang II, decrease P53 and P21 expression and caspase-3 activity, and reduce Ang II induced NRK-52E cell apoptosis. (PMID:19411745)
• A specific Klotho variant (rs577912) is linked to survival in end-stage renal disease patients initiating chronic hemodialysis. (PMID:19419323)
• We found a significant increase of the heterozygous Klotho genotype in the class of elderly people compared to young controls. (PMID:19421891)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kl	ENSDARG00000079862
mus_musculus	Kl	ENSMUSG00000058488
rattus_norvegicus	Kl	ENSRNOG00000001092
drosophila_melanogaster	CG9701	FBGN0036659
caenorhabditis_elegans		WBGENE00016848
caenorhabditis_elegans		WBGENE00017103

Paralogs (4): LCT (ENSG00000115850), KLB (ENSG00000134962), LCTL (ENSG00000188501), GBA3 (ENSG00000249948)

Protein

Protein identifiers

Klotho — Q9UEF7 (reviewed: Q9UEF7)

All UniProt accessions (1): Q9UEF7

UniProt curated annotations — full annotation on UniProt →

Function. May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D. Essential factor for the specific interaction between FGF23 and FGFR1. The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.

Subunit / interactions. Homodimer. Interacts with FGF23 and FGFR1.

Subcellular location. Cell membrane. Apical cell membrane Secreted Secreted.

Tissue specificity. Present in cortical renal tubules (at protein level). Soluble peptide is present in serum and cerebrospinal fluid. Expressed in kidney, placenta, small intestine and prostate. Down-regulated in renal cell carcinomas, hepatocellular carcinomas, and in chronic renal failure kidney.

Post-translational modifications. N-glycosylated.

Disease relevance. Tumoral calcinosis, hyperphosphatemic, familial, 3 (HFTC3) [MIM:617994] A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 239, and the second one lacks the essential Glu active site residue at position 872.

Polymorphism. Homozygosity for KL-VS allele is associated with decreased longevity and increased cardiovascular disease risk.

Miscellaneous. Defects in KL may be a cause of chronic renal failure complications. Predominates over the membrane form in all tissues examined.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UEF7-1	1, Membrane-bound	yes
Q9UEF7-2	2, Secreted

RefSeq proteins (1): NP_004786* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001360	Glyco_hydro_1	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR033132	GH_1_N_CS	Conserved_site

Pfam: PF00232

Catalyzed reactions (Rhea), 1 shown:

• a beta-D-glucuronoside + H2O = D-glucuronate + an alcohol (RHEA:17633)

UniProt features (124 total): strand 46, helix 40, turn 14, glycosylation site 7, sequence variant 7, chain 2, splice variant 2, topological domain 2, region of interest 2, signal peptide 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7YSH	ELECTRON MICROSCOPY	2.74
5W21	X-RAY DIFFRACTION	3
7YSW	ELECTRON MICROSCOPY	3.03
7YSU	ELECTRON MICROSCOPY	3.2
8TOH	ELECTRON MICROSCOPY	3.29
8UF8	ELECTRON MICROSCOPY	6.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UEF7-F1	89.48	0.74

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 (7): 283, 344, 607, 612, 694, 106, 159

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-190374	FGFR1c and Klotho ligand binding and activation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 256 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOBP_RESPONSE_TO_ANGIOTENSIN, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, chr13q13, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (13): negative regulation of systemic arterial blood pressure (GO:0003085), carbohydrate metabolic process (GO:0005975), energy reserve metabolic process (GO:0006112), determination of adult lifespan (GO:0008340), fibroblast growth factor receptor signaling pathway (GO:0008543), response to activity (GO:0014823), positive regulation of bone mineralization (GO:0030501), response to vitamin D (GO:0033280), norepinephrine biosynthetic process (GO:0042421), calcium ion homeostasis (GO:0055074), positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway (GO:0090080), response to angiotensin (GO:1990776), response to fibroblast growth factor (GO:0071774)

GO Molecular Function (9): beta-glucuronidase activity (GO:0004566), fibroblast growth factor receptor binding (GO:0005104), hormone activity (GO:0005179), vitamin D binding (GO:0005499), beta-glucosidase activity (GO:0008422), fibroblast growth factor binding (GO:0017134), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
Signaling by FGFR1	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 ligand binding and activation	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
primary metabolic process	1
energy derivation by oxidation of organic compounds	1
multicellular organismal process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
response to stimulus	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
response to vitamin	1
response to lipid	1
response to oxygen-containing compound	1
norepinephrine metabolic process	1
catecholamine biosynthetic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
MAPK cascade	1
fibroblast growth factor receptor signaling pathway	1
positive regulation of MAPK cascade	1
response to peptide hormone	1
response to growth factor	1
glucuronidase activity	1
growth factor receptor binding	1
receptor ligand activity	1
steroid binding	1
vitamin binding	1
glucosidase activity	1
growth factor binding	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

1483 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KL	FGF23	Q9GZV9	999
KL	FGFR1	P11362	997
KL	FGF8	P55075	990
KL	FGF20	Q9NP95	987
KL	FGF22	Q9HCT0	987
KL	FGF10	O15520	987
KL	FGF18	O76093	987
KL	FGFR4	P22455	987
KL	FGF16	O43320	987
KL	FGF9	P31371	987
KL	FGF4	P08620	986
KL	FGF6	P10767	986
KL	FGF5	P12034	986
KL	FGF3	P11487	986
KL	FGF17	O60258	986

IntAct

3 interactions, top by confidence:

A	B	Type	Score
MYO3B	CALU	psi-mi:“MI:0914”(association)	0.350
KL	rnb	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): KL (Affinity Capture-Western), SHANK1 (Affinity Capture-Western), MDM2 (Affinity Capture-Western), KL (Affinity Capture-Western), KL (Affinity Capture-Western), KL (Affinity Capture-MS), DDX58 (Affinity Capture-Western), KL (Affinity Capture-Western)

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	373
Likely benign	133
Benign	36

Top pathogenic / likely-pathogenic (0)

SpliceAI

1031 predictions. Top by Δscore:

Variant	Effect	Δscore
13:33017257:CTGG:C	donor_loss	1.0000
13:33017260:G:GG	donor_gain	1.0000
13:33017260:GTGA:G	donor_loss	1.0000
13:33061780:GGT:G	donor_loss	1.0000
13:33061781:GTA:G	donor_loss	1.0000
13:33061782:T:G	donor_loss	1.0000
13:33063843:TTCCA:T	acceptor_loss	1.0000
13:33063844:TCCA:T	acceptor_loss	1.0000
13:33063845:CCA:C	acceptor_loss	1.0000
13:33063846:CAGCC:C	acceptor_loss	1.0000
13:33063847:A:AG	acceptor_gain	1.0000
13:33063847:AGC:A	acceptor_loss	1.0000
13:33063848:G:GA	acceptor_gain	1.0000
13:33063848:GC:G	acceptor_gain	1.0000
13:33063848:GCC:G	acceptor_gain	1.0000
13:33063848:GCCC:G	acceptor_gain	1.0000
13:33063848:GCCCA:G	acceptor_gain	1.0000
13:33017255:TCCTG:T	donor_gain	0.9900
13:33017258:TG:T	donor_gain	0.9900
13:33017259:GG:G	donor_gain	0.9900
13:33017262:GAGT:G	donor_loss	0.9900
13:33055045:A:AG	acceptor_gain	0.9900
13:33055046:G:GG	acceptor_gain	0.9900
13:33055046:GCC:G	acceptor_gain	0.9900
13:33061781:G:GG	donor_gain	0.9900
13:33063838:T:TA	acceptor_gain	0.9900
13:33017257:CTG:C	donor_gain	0.9800
13:33053761:TCATA:T	acceptor_loss	0.9800
13:33053762:CATA:C	acceptor_loss	0.9800
13:33053764:TAGG:T	acceptor_loss	0.9800

AlphaMissense

6668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:33016897:T:A	W153R	0.993
13:33016897:T:C	W153R	0.993
13:33017059:T:A	W207R	0.991
13:33017059:T:C	W207R	0.991
13:33054073:A:C	S376R	0.990
13:33054075:T:A	S376R	0.990
13:33054075:T:G	S376R	0.990
13:33055189:G:C	K491N	0.990
13:33055189:G:T	K491N	0.990
13:33016566:G:C	W42C	0.989
13:33016566:G:T	W42C	0.989
13:33017252:T:C	L271P	0.989
13:33055112:T:A	W466R	0.989
13:33055112:T:C	W466R	0.989
13:33053851:T:A	W302R	0.988
13:33053851:T:C	W302R	0.988
13:33053923:T:A	W326R	0.988
13:33053923:T:C	W326R	0.988
13:33055100:G:C	D462H	0.988
13:33061129:T:A	W684R	0.987
13:33061129:T:C	W684R	0.987
13:33017061:G:C	W207C	0.986
13:33017061:G:T	W207C	0.986
13:33017140:T:A	W234R	0.986
13:33017140:T:C	W234R	0.986
13:33061048:T:A	W657R	0.986
13:33061048:T:C	W657R	0.986
13:33061187:T:C	L703P	0.986
13:33061279:T:A	W734R	0.986
13:33061279:T:C	W734R	0.986

dbSNP variants (sampled 300 via entrez): RS1000071745 (13:33061914 C>T), RS1000099608 (13:33023003 T>C), RS1000154838 (13:33034318 T>G), RS1000270712 (13:33028475 A>C), RS1000291906 (13:33059110 C>G,T), RS1000323772 (13:33039446 G>T), RS1000324076 (13:33058704 T>C), RS1000328618 (13:33041234 T>A), RS1000375326 (13:33033141 C>A,G), RS1000425999 (13:33032802 A>C), RS1000445864 (13:33066056 G>A), RS1000501426 (13:33023433 A>G), RS1000609323 (13:33029815 A>G), RS1000640085 (13:33057420 G>A), RS1000641829 (13:33029649 T>A,C)

Disease associations

OMIM: gene MIM:604824 | disease phenotypes: MIM:617994, MIM:211900

GenCC curated gene-disease

Disease	Classification	Inheritance
tumoral calcinosis, hyperphosphatemic, familial, 1	Supportive	Autosomal recessive
tumoral calcinosis, hyperphosphatemic, familial, 3	Limited	Autosomal recessive

Mondo (4): tumoral calcinosis, hyperphosphatemic, familial, 3 (MONDO:0060715), amenorrhea (MONDO:0001836), tumoral calcinosis, hyperphosphatemic, familial, 1 (MONDO:0100252), (MONDO:0008897)

Orphanet (1): Familial tumoral calcinosis (Orphanet:53715)

HPO phenotypes

16 total (17 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000103	Polyuria
HP:0000787	Nephrolithiasis
HP:0000938	Osteopenia
HP:0001959	Polydipsia
HP:0002315	Headache
HP:0002514	Cerebral calcification
HP:0002905	Hyperphosphatemia
HP:0003072	Hypercalcemia
HP:0003165	Elevated circulating parathyroid hormone level
HP:0005450	Calvarial osteosclerosis
HP:0006051	Metacarpal periosteal thickening
HP:0008208	Parathyroid hyperplasia
HP:0012378	Fatigue
HP:0025441	Achilles tendon calcification
HP:0031415	High serum calcitriol
HP:0000141	Amenorrhea

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST004894_119	Type 2 diabetes	9.000000e-13
GCST004894_15	Type 2 diabetes	6.000000e-07
GCST005531_78	Multiple sclerosis	1.000000e-06
GCST006867_122	Type 2 diabetes	2.000000e-11
GCST007100_10	Asthma exacerbations in inhaled corticosteroid treatment	3.000000e-06
GCST007847_4	Type 2 diabetes	3.000000e-15
GCST007899_18	Fasting blood glucose	2.000000e-06
GCST008362_51	Birth weight	3.000000e-08
GCST009379_357	Type 2 diabetes	8.000000e-10
GCST010118_92	Type 2 diabetes	3.000000e-18
GCST011741_41	LDL cholesterol levels in HIV infection	7.000000e-07
GCST90026416_18	Mild age-related type 2 diabetes	8.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007614	asthma exacerbation measurement
EFO:0004344	birth weight
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523485 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs36217263	Efficacy	3	Beta Blocking Agents

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs211247	KL		0.00	0
rs36217263	KL	3	2.75	1	Beta Blocking Agents

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.2.1.- Glycosidases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects reaction, increases expression, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation, decreases reaction	2
Indican	decreases expression, decreases reaction, increases expression	2
Phosphates	affects abundance, affects reaction, decreases uptake, increases reaction	2
fluorene-9-bisphenol	increases expression	1
propionaldehyde	decreases expression	1
chlorophyllin	decreases reaction, increases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression, decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects cotreatment, increases expression	1
pregna-4,17-diene-3,16-dione	affects reaction, decreases reaction, increases expression, decreases expression	1
ligustilide	increases expression	1
sodium chlorate	decreases expression	1
puerarin	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	decreases expression	1
isohelenin	decreases expression, decreases reaction	1
pomiferin	decreases expression	1
osajin	decreases expression	1
rosavin	decreases expression	1
Arsenic Trioxide	increases expression	1
Microplastics	decreases expression, increases abundance	1
Acetylcysteine	decreases expression, decreases reaction, increases expression	1
Cadmium	affects methylation	1
Cholecalciferol	affects cotreatment, increases expression	1
Cocaine	increases expression	1
Hydrogen Peroxide	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Oxygen	increases expression, decreases reaction, decreases expression, affects reaction	1
Phenobarbital	decreases expression	1
Polystyrenes	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4414719	ADMET	Prodrug conversion assessed as recombinant human alpha-klotho mediated curcumin-glucuronide hydrolysis incubated for 24 hrs by LC-MS analysis	Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone. — J Nat Prod

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0NM	HEK293-KL	Transformed cell line	Female
CVCL_E0UG	Ubigene Hep G2 KL KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
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
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants
NCT00243607	Not specified	COMPLETED	Hydrotherapy Against Menopausal Symptoms in Breast Cancer Survivors
NCT00260286	Not specified	COMPLETED	Effects of Gynecological Age on LH Sensitivity to Energy Availability
NCT00456274	Not specified	UNKNOWN	Baselines in Reproductive Disorders
NCT00589654	Not specified	ACTIVE_NOT_RECRUITING	Menstrual Cycle Maintenance and Quality of Life: A Prospective Study
NCT01423487	Not specified	WITHDRAWN	Efficacy and Safety of Metformin in Preventing Patients With Risperidone From Weight Gain and Amenorrhea
NCT01500447	Not specified	RECRUITING	Inherited Reproductive Disorders
NCT01511588	Not specified	COMPLETED	Hormonal Regulation of Puberty and Fertility
NCT01785719	Not specified	COMPLETED	Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss
NCT01927432	Not specified	COMPLETED	Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
NCT02224976	Not specified	COMPLETED	Effect of Intense Training on Ovarian Function and Bone Turnover
NCT04135729	Not specified	COMPLETED	Mental Health in Fitness Instructors
NCT04424576	Not specified	RECRUITING	Ovarian Morphology in Girls
NCT04938622	Not specified	COMPLETED	Bioenergetics of Exercise-Induced Menstrual Disturbances
NCT06280807	Not specified	RECRUITING	Observation of Environment and Reproductive-Endocrine Effects
NCT06800170	Not specified	RECRUITING	Treatment of Menstrual Cycle Alterations in Adolescents
NCT07015476	Not specified	RECRUITING	Retrospective Observational Evaluation of the Bone Mineral Density Outcome in Young Women With Amenorrhea
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice
NCT07612735	Not specified	NOT_YET_RECRUITING	Effects of Resistance Training on Women With Functional Hypothalamic Amenorrhea