METTL4

protein-coding

methyltransferase 4, N6-adenosine, the group of 7BS N6-adenosine DNA/RNA methyltransferases

Gene summary

Enables RNA methyltransferase activity and site-specific DNA-methyltransferase (adenine-specific) activity. Contributes to mRNA N6-methyladenosine dioxygenase activity. Involved in regulation of gene expression; regulation of mitochondrial DNA replication; and snRNA (adenine-N6)-methylation. Located in cytosol; mitochondrial matrix; and nucleus. Part of RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_022840.5

Inheritance

ClinVar variants

P:1U:61

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr18:2,537,525-2,571,509

External References & Databases

Ensembl (ENSG00000101574)

Transcript & Mutation Effects

hg38 • Region Span ~34.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published PMID: 34452636 – Reports a consanguineous family with severe intellectual disability . Family 1 – Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = 1.0; segregation (additional affected siblings counted conservatively; affected sibs not scored as independent probands) = 0.5; case-control = 0; Family 1 total = 1.5. PMID: 27457812 – Reports a consanguineous family with autosomal recessive intellectual disability. Family 2 –.one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = 1.0; segregation = 0; case-control = 0; Family 2 total = 1.0. Published genetic evidence total = 2.5 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0. Our cases total = 1.0 / 12 Total genetic evidence (published + our cases) 2.5 + 1.0 = 3.5 / 12 Experimental evidence – Published Functional data in the literature demonstrate that METTL4 encodes an RNA methyltransferase involved in U2 snRNA N6-methyladenosine modification and regulation of RNA splicing, supporting biological plausibility for a neurodevelopmental phenotype. Gene function / biological plausibility = 0.5; Experimental evidence total = 0.5 / 6 Overall score Genetic evidence = 3.5 Experimental evidence = 0.5 Overall score = 4.0

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to METTL4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 54

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022840.5. 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						0
missense			59 clinvar			59
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	0	1	61	0	0	62

Highest pathogenic variant AF is 0.00006302111

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022840.5	RefSeq	NP_073751.3	8	MANE Select
ENST00000574538.2	Ensembl	ENSP00000458290.1	8	MANE Select
NM_001308401.2	RefSeq	NP_001295330.1	7	Standard
ENST00000319888.10	Ensembl	ENSP00000320349.6	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA methylation on adenine

Molecular Function

nucleic acid binding
site-specific DNA-methyltransferase (adenine-specific) activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000574538
Coding exons: 8
Length: 33985
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 65
Defined: 125742
p: 0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.392	223	240	0.929	0.0000116	3112
Missense (PolyPhen)		54	64.581	0.83617		836
Synonymous	-0.0732	83	82.2	1.01	0.00000388	872
Loss of Function	1.73	15	24.2	0.620	0.00000134	288

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00036	0.00036	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable methyltransferase. {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.815
RVIS EVS: 0.55
RVIS percentile EVS: 81.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.468

Gene Damage Prediction

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