KLHL8

protein-coding

kelch like family member 8, the group of Kelch like|BTB domain containing

Gene summary

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Involved in protein ubiquitination and ubiquitin-dependent protein catabolic process. Located in nucleoplasm. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_020803.5

Inheritance

—

ClinVar variants

U:56

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr4:87,160,103-87,240,314

External References & Databases

Ensembl (ENSG00000145332)

Transcript & Mutation Effects

hg38 • Region Span ~80.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL8 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 52

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020803.5. 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			1
missense			54 clinvar			54
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	56	0	0	56

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020803.5	RefSeq	NP_065854.3	9	MANE Select
ENST00000273963.10	Ensembl	ENSP00000273963.5	9	MANE Select
NM_001292003.2	RefSeq	NP_001278932.1	9	Standard
NM_001292006.2	RefSeq	NP_001278935.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein ubiquitination

Cellular Component

nucleoplasm
Cul3-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273963
Coding exons: 9
Length: 80212
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 69
Defined: 125746
p: 0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.23	222	337	0.659	0.0000166	4091
Missense (PolyPhen)		76	140.88	0.53947		1648
Synonymous	1.01	102	116	0.880	0.00000569	1184
Loss of Function	2.63	14	29.4	0.476	0.00000177	332

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00028	0.00028	rare
South Asian	0.00030	0.00029	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for The BCR(KLHL8) ubiquitin ligase complex mediates ubiquitination and degradation of RAPSN. {ECO:0000269|PubMed:19158078}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.596
RVIS EVS: -0.69
RVIS percentile EVS: 15.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.846

Gene Damage Prediction

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