MLKL

mixed lineage kinase domain like pseudokinase

Basic information

Region (hg38): 16:74671855-74700960

Links

ENSG00000168404

∙ NCBI:197259 ∙ OMIM:615153 ∙ HGNC:26617 ∙ Uniprot:Q8NB16 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MLKL gene.

not_specified (72 variants)
not_provided (6 variants)
Inflammatory_bowel_disease (1 variants)
Chronic_multifocal_osteomyelitis (1 variants)
Biotinidase_deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MLKL gene is commonly pathogenic or not. These statistics are base on transcript: NM_000152649.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous				2 clinvar	2 clinvar	4
missense			66 clinvar	8 clinvar	2 clinvar	76
nonsense						0
start loss					1	1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	66	10	5

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MLKL	protein_coding	protein_coding	ENST00000308807	10	29106

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.09e-14	0.0593	125623	0	124	125747	0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.45	335	268	1.25	0.0000153	3081
Missense in Polyphen		73	64.082	1.1392		757
Synonymous	-0.208	103	100	1.03	0.00000565	886
Loss of Function	0.596	23	26.3	0.875	0.00000148	303

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000633	0.000633
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.00174	0.00174
Finnish	0.00	0.00
European (Non-Finnish)	0.000222	0.000220
Middle Eastern	0.00174	0.00174
South Asian	0.00157	0.00154
Other	0.000334	0.000326

dbNSFP

Source: dbNSFP

Function: FUNCTION: Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process. Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). {ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}.;
Pathway: TNF signaling pathway - Homo sapiens (human);Necroptosis - Homo sapiens (human);DNA Damage Response (only ATM dependent);Regulated Necrosis;Programmed Cell Death;RIPK1-mediated regulated necrosis (Consensus)

Recessive Scores

pRec: 0.0487

Intolerance Scores

loftool: 0.455
rvis_EVS: 0.96
rvis_percentile_EVS: 90.15

Haploinsufficiency Scores

pHI: 0.0272
hipred: N
hipred_score: 0.147
ghis: 0.396

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.889

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Mlkl
Phenotype: homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);

Gene ontology

Biological process: MAPK cascade;cell surface receptor signaling pathway;activation of JNKK activity;activation of JUN kinase activity;protein homotrimerization;necroptotic process
Cellular component: cytoplasm;cytosol;plasma membrane
Molecular function: protein kinase activity;protein serine/threonine kinase activity;JUN kinase kinase kinase activity;protein binding;ATP binding;protein kinase binding;protein-containing complex binding