METTL9

Chr 16

methyltransferase 9, His-X-His N1(pi)-histidine

Also known as: CGI-81, DREV, DREV1, PAP1, hMETTL9

NCBI Gene: 51108 ENSG00000197006 UniProt: Q9H1A3

The protein is a methyltransferase that catalyzes 1-methylhistidine modification of target proteins containing His-x-His motifs, which may affect metal binding properties of these proteins. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically manifesting in early childhood. The gene shows high constraint against loss-of-function variants (pLI = 0.80, LOEUF = 0.45), suggesting intolerance to heterozygous protein loss.

ResearchSummary from RefSeq, UniProt

Enables protein-L-histidine N-pros-methyltransferase activity. Predicted to be involved in methylation. Is active in endoplasmic reticulum and mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOEUF 0.45

Clinical Summary— METTL9

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 66 VUS of 93 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.804

Z-score 2.99

OE 0.14 (0.06–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.62Z-score

OE missense 0.41 (0.34–0.51)

65 obs / 157.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.45)

0≤0.351.4

Missense OE?0.41 (0.34–0.51)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 2 / 14.1Missense obs/exp: 65 / 157.5Syn Z: -0.50

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS66

Likely Benign4

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	66	0	0	66
Likely Benign	3	0	1	4
Benign	0	0	0	0
Total	69	1	1	71

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

View in ClinVar →

77 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap METTL9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →