METTL14

Chr 4

methyltransferase 14, N6-adenosine-methyltransferase non-catalytic subunit

Also known as: hMETTL14

NCBI Gene: 57721 ENSG00000145388 UniProt: Q9HCE5 OMIM: 616504

METTL14 forms a heterodimer with METTL3 that functions as an N6-methyltransferase complex, methylating adenosine residues in mRNAs to regulate mRNA stability, circadian clock function, and cortical neurogenesis. Biallelic mutations cause developmental delay, intellectual disability, and microcephaly with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.607), reflecting its essential role in neurodevelopment and cellular differentiation.

OMIM ResearchSummary from RefSeq, UniProt

Enables mRNA binding activity and mRNA m(6)A methyltransferase activity. Involved in mRNA modification; mRNA splicing, via spliceosome; and mRNA stabilization. Located in nucleoplasm. Part of RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

442

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.001

Z-score 3.15

OE 0.36 (0.22–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.74Z-score

OE missense 0.51 (0.44–0.59)

124 obs / 244.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.36 (0.22–0.61)

0≤0.351.4

Missense OE?0.51 (0.44–0.59)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 10 / 27.9Missense obs/exp: 124 / 244.5Syn Z: 0.36

Background carrier burden — how many people carry a rare variant somewhere in METTL14?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

424 rare PASS variants

Rare truncating (LoF)

1 in 1,200

88 rare PASS variants

Rare synonymous (reference)

1 in 200

163 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for METTL14. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 260	1 in 3,800
South Asian	~43k	1 in 250	1 in 460
Remaining (unassigned)	~30k	1 in 220	1 in 4,200
European (Finnish)	~27k	1 in 230	1 in 480
Admixed American	~22k	1 in 180	1 in 2,300
African / African American	~21k	1 in 170	1 in 1,500
East Asian	~20k	1 in 170	1 in 770
Ashkenazi Jewish	~13k	1 in 430	1 in 1,700
Middle Eastern	~2,884	1 in 410	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 11 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 9 marginal. Genomes: all 11.? see exons ↓