METTL18

Chr 1

methyltransferase 18, RPL3 N3(tau)-histidine

Also known as: AsTP2, C1orf156, HPM1

NCBI Gene: 92342 ENSG00000171806 UniProt: O95568 OMIM: 615255

The METTL18 protein is a histidine methyltransferase that monomethylates ribosomal protein RPL3 to regulate translation elongation, particularly slowing ribosome traversal on tyrosine codons to allow proper protein folding. Mutations cause autosomal recessive intellectual disability. The gene shows low constraint to loss-of-function mutations based on population genetics data.

OMIM ResearchSummary from RefSeq, UniProt

Enables heat shock protein binding activity and protein-L-histidine N-tele-methyltransferase activity. Involved in peptidyl-lysine monomethylation; regulation of gene expression; and regulation of ribosome biogenesis. Located in cytosol and nucleolus. Part of protein-containing complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.39

Clinical Summary— METTL18

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

41 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.39LOEUF

pLI 0.000

Z-score 0.68

OE 0.77 (0.45–1.39)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.12Z-score

OE missense 0.97 (0.86–1.10)

174 obs / 178.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.45–1.39)

0≤0.351.4

Missense OE?0.97 (0.86–1.10)

0≤0.61.4

Synonymous OE?0.67

0≤1.21.6

LoF obs/exp: 8 / 10.4Missense obs/exp: 174 / 178.5Syn Z: 2.05

This gene — mechanism propensity

0.6550th %ile

GOF

0.4382th %ile

LOF

0.3260th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign3

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	41	0	41
Likely Benign	3	0	3
Benign	0	1	1
Total	44	1	45

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

22 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap METTL18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →