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.

• Maturity onset diabetes mellitus in young (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					2	2
missense	1		28	8	1	38
nonsense						0
start loss					1	1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	1	0	28	8	4

Highest pathogenic variant AF is 0.0000197

Variants in MLKL

This is a list of pathogenic ClinVar variants found in the MLKL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-74672520-G-A		not specified	Uncertain significance (Mar 15, 2024)
16-74674989-T-C		not specified	Uncertain significance (Jun 30, 2023)
16-74674990-G-A		not specified	Likely benign (Jun 17, 2024)
16-74674992-G-A		not specified	Uncertain significance (Jun 16, 2024)
16-74675016-C-T			Uncertain significance (Jun 01, 2022)
16-74675089-C-T		not specified	Likely benign (Nov 03, 2022)
16-74675362-C-T		not specified	Likely benign (May 23, 2024)
16-74675380-G-A		not specified	Likely benign (Dec 28, 2023)
16-74675617-A-G		not specified	Uncertain significance (Oct 05, 2021)
16-74675637-T-C		not specified	Uncertain significance (Mar 18, 2024)
16-74675667-G-C		not specified	Uncertain significance (Sep 28, 2022)
16-74675667-G-T		not specified	Uncertain significance (May 04, 2022)
16-74675670-G-A		not specified	Uncertain significance (Apr 13, 2022)
16-74675674-G-T		not specified	Likely benign (Dec 11, 2023)
16-74675724-C-G		not specified	Uncertain significance (Aug 21, 2023)
16-74682652-G-A		not specified	Likely benign (May 09, 2023)
16-74682660-C-T		Maturity onset diabetes mellitus in young	Pathogenic (Dec 16, 2020)
16-74682682-G-C		not specified	Uncertain significance (Nov 17, 2023)
16-74682691-G-A		not specified	Uncertain significance (Dec 08, 2021)
16-74682727-G-A			Benign (May 18, 2018)
16-74685498-T-C		not specified	Uncertain significance (Dec 16, 2023)
16-74691297-T-C			Benign (Jun 18, 2018)
16-74691302-T-C		not specified	Uncertain significance (Jun 28, 2022)
16-74691303-G-T		not specified	Uncertain significance (Jun 10, 2022)
16-74691385-G-A		not specified	Uncertain significance (Jun 16, 2022)

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