MLKL

protein-coding

mixed lineage kinase domain like pseudokinase

Gene summary

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis. High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]

MANE transcript

NM_152649.4

Inheritance

—

ClinVar variants

U:83B:15

Top phenotype

Inflammatory bowel disease

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr16:74,671,855-74,700,960

External References & Databases

Ensembl (ENSG00000168404)

Transcript & Mutation Effects

hg38 • Region Span ~29.1 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 MLKL variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 82

not providedTotal: 6

Inflammatory bowel diseaseTotal: 1

Chronic multifocal osteomyelitisTotal: 1

Biotinidase deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152649.4. 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 clinvar	2 clinvar	6
missense			78 clinvar	8 clinvar	2 clinvar	88
nonsense			1 clinvar			1
start loss					1 clinvar	1
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	83	10	5	98

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152649.4	RefSeq	NP_689862.1	10	MANE Select
ENST00000308807.12	Ensembl	ENSP00000308351.7	10	MANE Select
NM_001142497.3	RefSeq	NP_001135969.1	5	Standard
ENST00000306247.11	Ensembl	ENSP00000303118.7	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TNF signaling pathway - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
DNA Damage Response (only ATM dependent)
Regulated Necrosis
Programmed Cell Death

Biological Process

MAPK cascade
cell surface receptor signaling pathway
activation of JNKK activity
activation of JUN kinase activity
protein homotrimerization

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
JUN kinase kinase kinase activity
protein binding
ATP binding

Cellular Component

cytoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308807
Coding exons: 10
Length: 29106
Individuals with no LoFs: 125623
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125747
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.45	335	268	1.25	0.0000153	3081
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00039	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0017	0.0017	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.0016	0.0015	notable
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.0487

Intolerance Scores

LoFtool: 0.455
RVIS EVS: 0.96
RVIS percentile EVS: 90.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.889

Gene Damage Prediction

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