KLHL25

protein-coding

kelch like family member 25, the group of BTB domain containing|Kelch like|MicroRNA protein coding host genes

Gene summary

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; protein ubiquitination; and regulation of fatty acid metabolic process. Located in cytoplasm. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_022480.4

Inheritance

—

ClinVar variants

U:132B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.49

Max pathogenic AF

—

Genomic locus

chr15:85,759,326-85,794,925

External References & Databases

Ensembl (ENSG00000183655)

Transcript & Mutation Effects

hg38 • Region Span ~35.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL25 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 129

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022480.4. 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			2 clinvar			2
missense			129 clinvar	1 clinvar		130
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	132	1	0	133

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022480.4	RefSeq	NP_071925.2	1	MANE Select
ENST00000337975.6	Ensembl	ENSP00000336800.5	1	MANE Select
ENST00000853251.1	Ensembl	ENSP00000523310.1	1	Standard
ENST00000853251.2	Ensembl	ENSP00000523310.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation

Biological Process

regulation of translational initiation
ubiquitin-dependent protein catabolic process
protein ubiquitination
post-translational protein modification

Cellular Component

cytoplasm
cytosol
Cul3-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337975
Coding exons: 1
Length: 35708
Individuals with no LoFs: 125661
Homozygous LoFs: 2
Heterozygous LoFs: 85
Defined: 125748
p: 0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.43	478	398	1.20	0.0000279	3855
Missense (PolyPhen)		236	197.33	1.196		1883
Synonymous	-1.63	208	180	1.15	0.0000137	1221
Loss of Function	-1.61	19	12.8	1.49	5.53e-7	155

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000097	0.000092	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.0011	0.0011	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for translational homeostasis. The BCR(KLHL25) ubiquitin ligase complex acts by mediating ubiquitination of hypophosphorylated EIF4EBP1 (4E-BP1): ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) probably serves as a homeostatic mechanism to maintain translation and prevent eIF4E inhibition when eIF4E levels are low. The BCR(KLHL25) complex does not target EIF4EBP1 (4E-BP1) when it is hyperphosphorylated or associated with eIF4E. {ECO:0000269|PubMed:22578813}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.502
RVIS EVS: -1.57
RVIS percentile EVS: 3.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.852

Gene Damage Prediction

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