KLB

protein-coding

klotho beta, the group of MicroRNA protein coding host genes|Glycoside hydrolase family 1

Gene summary

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. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_175737.4

Inheritance

ClinVar variants

P:1U:156B:70

Top phenotype

hypogonadotropic hypogonadism

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr4:39,406,930-39,451,533

External References & Databases

Ensembl (ENSG00000134962)

Transcript & Mutation Effects

hg38 • Region Span ~44.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLB variants in ClinVar

8 Conditions Cataloged

not providedTotal: 122

not specifiedTotal: 121

KLB-related disorderTotal: 12

AmenorrheaTotal: 2

Martsolf syndrome 1Total: 2

Male infertility with azoospermia or oligozoospermia due to single gene mutationTotal: 1

Hypogonadotropic hypogonadismTotal: 1

Ocular motility diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175737.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	37 clinvar	9 clinvar	47
missense			149 clinvar	18 clinvar	6 clinvar	173
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar	4 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	156	55	15	227

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_175737.4	RefSeq	NP_783864.1	5	MANE Select
ENST00000257408.5	Ensembl	ENSP00000257408.4	5	MANE Select
ENST00000859482.1	Ensembl	ENSP00000529541.1	5	Standard
ENST00000859482.2	Ensembl	ENSP00000529541.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
PI-3K cascade:FGFR4
Disease
betaKlotho-mediated ligand binding
FGFR4 ligand binding and activation

Biological Process

MAPK cascade
carbohydrate metabolic process
positive regulation of cell population proliferation
fibroblast growth factor receptor signaling pathway
phosphatidylinositol-3-phosphate biosynthetic process

Molecular Function

hydrolase activity, hydrolyzing O-glycosyl compounds
Ras guanyl-nucleotide exchange factor activity
fibroblast growth factor receptor binding
protein binding
1-phosphatidylinositol-3-kinase activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257408
Coding exons: 5
Length: 44684
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 125748
p: 0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.88	477	608	0.785	0.0000343	6833
Missense (PolyPhen)		136	237.34	0.57302		2823
Synonymous	0.351	251	258	0.972	0.0000164	2069
Loss of Function	4.62	12	45.7	0.263	0.00000270	451

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00037	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00045	0.00045	rare
South Asian	0.0013	0.0013	notable
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.0983

Intolerance Scores

LoFtool: 0.618
RVIS EVS: 0.34
RVIS percentile EVS: 73.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.219

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium