METTL23

protein-coding

methyltransferase like 23

Gene summary

The protein encoded by this gene functions as a transcription factor regulator in the transcriptional pathway for human cognition. It is a partner of the alpha subunit of the GA-binding protein transcription factor. Mutations in this gene cause mild autosomal recessive intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

Previous symbols:

C17orf95

MANE transcript

NM_001080510.5

Inheritance

ClinVar variants

P:21U:45B:8

Top phenotype

Intellectual developmental disorder, autosomal recessive 44

gnomAD constraint

pLI —, LoF o/e 1.11

Max pathogenic AF

—

Genomic locus

chr17:76,726,830-76,733,936

External References & Databases

Ensembl (ENSG00000181038)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual disability, autosomal recessive 44DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014409

Submitter: G2P

intellectual disability, autosomal recessive 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014409

Submitter: PanelApp Australia

intellectual disability, autosomal recessive 44MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014409

Submitter: Ambry Genetics

intellectual disability, autosomal recessive 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014409

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

*METTL23* was first reported in relation to autosomal recessive intellectual disability in 2014 (PMIDs: 24501276, 24626631). Clinical features consistently reported in affected individuals include intellectual disability, global developmental delay, and various dysmorphic facial features such as a depressed nasal bridge and thin vermilion border (PMID: 39026940). Six variants (including splicing, frameshift, and a single missense variant) reported in 6 probands across 5 publications (PMIDs: 39026940, 32878022, 32439618, 24501276, 24626631) are included in this curation. The homozygous missense variant lacks functional evidence of pathogenicity and was assigned only 0.2 points. Within three of the families, the variants were found to segregate with disease across 11 individuals (PMIDs: 24626631, 24501276, 32878022). The mechanism of pathogenicity appears to be loss of function (PMIDs: 39026940, 24626631). This gene-disease relationship is also supported by experimental evidence including protein interactions and functional studies (PMID: 24501276). In summary, there is definitive evidence to support the relationship between *METTL23* and autosomal recessive intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on February 17, 2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 44AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24501276; 24626631

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to METTL23 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 39

not providedTotal: 26

Intellectual disability, autosomal recessive 44Total: 24

not specifiedTotal: 7

METTL23-related disorderTotal: 4

Intellectual disabilityTotal: 2

METTL23-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080510.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				2 clinvar		2
missense			40 clinvar	6 clinvar		46
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift	6 clinvar	11 clinvar	2 clinvar			19
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	1 clinvar			4
Total	9	12	45	8	0	74

Highest pathogenic variant AF is 0.00015365875

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080510.5	RefSeq	NP_001073979.3	4	MANE Select
ENST00000341249.11	Ensembl	ENSP00000341543.5	4	MANE Select
NM_001206983.3	RefSeq	NP_001193912.1	4	Standard
NM_001206984.3	RefSeq	NP_001193913.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

methylation
positive regulation of transcription by RNA polymerase II
cognition

Molecular Function

protein binding
transcription factor binding
methyltransferase activity
heat shock protein binding

Cellular Component

nucleus
cytoplasm
integral component of membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341249
Coding exons: 4
Length: 7107
Individuals with no LoFs: 124553
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 124638
p: 0.000341

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.973	123	96.1	1.28	0.00000423	1227
Missense (PolyPhen)		37	34.202	1.0818		442
Synonymous	-0.964	40	33.0	1.21	0.00000141	368
Loss of Function	-0.299	10	9.03	1.11	3.83e-7	108

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00034	0.00032	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00052	0.00050	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00044	0.00042	rare
South Asian	0.00027	0.00026	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable methyltransferase. {ECO:0000250}.;
Disease: DISEASE: Mental retardation, autosomal recessive 44 (MRT44) [MIM:615942]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT44 manifestations include mild to severe cognitive impairment, delayed psychomotor development, seizures in some patients, and dysmorphic features. {ECO:0000269|PubMed:24501276, ECO:0000269|PubMed:24626631}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0822

Intolerance Scores

RVIS EVS: 0.35
RVIS percentile EVS: 74.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium