METTL8

Chr 2

methyltransferase 8, tRNA N3-cytidine

Also known as: TIP

NCBI Gene: 79828 ENSG00000123600 UniProt: Q9H825 OMIM: 609525

Enables mRNA methyltransferase activity and tRNA (cytidine-N3)-methyltransferase activity. Involved in RNA metabolic process and positive regulation of mitochondrial translation. Is active in mitochondrial matrix. [provided by Alliance of Genome Resources, Jun 2026]

OMIM Research

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.33

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.33LOEUF

pLI 0.000

Z-score 0.44

OE 0.89 (0.61–1.33)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.91 (0.80–1.03)

170 obs / 187.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.61–1.33)

0≤0.351.4

Missense OE?0.91 (0.80–1.03)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 17 / 19.1Missense obs/exp: 170 / 187.5Syn Z: 0.51

Background carrier burden — how many people carry a rare variant somewhere in METTL8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

509 rare PASS variants

Rare truncating (LoF)

1 in 490

88 rare PASS variants

Rare synonymous (reference)

1 in 600

146 rare PASS variants

Rare missense and truncating variants are carried at similar rates in METTL8; this gene does not show strong loss-of-function constraint by this measure. 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 100	1 in 1,000
South Asian	~43k	1 in 75	1 in 430
Remaining (unassigned)	~30k	1 in 100	1 in 240
European (Finnish)	~27k	1 in 940	≈ 1 in 8,600
Admixed American	~22k	1 in 110	1 in 230
African / African American	~21k	1 in 60	1 in 670
East Asian	~20k	1 in 110	1 in 800
Ashkenazi Jewish	~13k	1 in 570	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 97	1 in 220

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 9 coding exons well covered in gnomAD exomes; exons 8, 9 marginal. Genomes: all 9.? see exons ↓