METTL4

Chr 18

methyltransferase 4, N6-adenosine

Also known as: HsT661

NCBI Gene: 64863 ENSG00000101574 UniProt: Q8N3J2 OMIM: 619626

METTL4 encodes a methyltransferase that adds methyl groups to adenine residues in both RNA and DNA, regulating RNA splicing through snRNA modification and controlling mitochondrial transcript levels and DNA copy number. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.95

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.000

Z-score 1.73

OE 0.62 (0.41–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.39Z-score

OE missense 0.93 (0.83–1.04)

223 obs / 240.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.41–0.95)

0≤0.351.4

Missense OE?0.93 (0.83–1.04)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 24.2Missense obs/exp: 223 / 240.1Syn Z: -0.07

Background carrier burden — how many people carry a rare variant somewhere in METTL4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

586 rare PASS variants

Rare truncating (LoF)

1 in 780

96 rare PASS variants

Rare synonymous (reference)

1 in 230

175 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for METTL4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓