KLHDC2

protein-coding

kelch domain containing 2

Gene summary

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nuclear body and nuclear membrane. Is active in Cul2-RING ubiquitin ligase complex and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_014315.3

Inheritance

—

ClinVar variants

U:42

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr14:49,768,130-49,786,385

External References & Databases

Ensembl (ENSG00000165516)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 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 KLHDC2 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 33

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014315.3. 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						0
missense			34 clinvar			34
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	42	0	0	42

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014315.3	RefSeq	NP_055130.1	13	MANE Select
ENST00000298307.10	Ensembl	ENSP00000298307.5	13	MANE Select
ENST00000554589.5	Ensembl	ENSP00000451439.1	12	Standard
ENST00000554589.6	Ensembl	ENSP00000451439.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

nucleus
nuclear body
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000298307
Coding exons: 13
Length: 15584
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125748
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.927	175	213	0.821	0.0000100	2660
Missense (PolyPhen)		48	73.314	0.65472		874
Synonymous	1.35	57	71.5	0.797	0.00000350	724
Loss of Function	3.41	8	27.2	0.294	0.00000128	333

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.000094	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0011	0.0011	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Represses CREB3-mediated transcription by interfering with CREB3-DNA binding. {ECO:0000269|PubMed:11384994}.;

Recessive Scores

pRec: 0.144

Intolerance Scores

RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.935

Gene Damage Prediction

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