ALKBH8

protein-coding

alkB homolog 8, tRNA methyltransferase, the group of 7BS DNA/RNA methyltransferases|RNA binding motif containing|Alkylation repair homologs

Gene summary

Enables tRNA (uridine) methyltransferase activity; tRNA binding activity; and zinc ion binding activity. Involved in DNA damage response; tRNA methylation; and tRNA wobble uridine modification. Located in cytosol and nucleoplasm. Implicated in autosomal recessive intellectual developmental disorder 71. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_138775.3

Inheritance

ClinVar variants

P:10U:119B:49

Top phenotype

Intellectual developmental disorder, autosomal recessive 71

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr11:107,502,727-107,565,742

External References & Databases

Ensembl (ENSG00000137760)

Transcript & Mutation Effects

hg38 • Region Span ~63.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 71STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032789

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 71DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032789

Submitter: G2P

intellectual developmental disorder, autosomal recessive 71LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032789

Submitter: Ambry Genetics

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 71STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032789

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 71AR

Manifestation: Craniofacial; Genitourinary; 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: 31079898

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALKBH8 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 129

not providedTotal: 63

Intellectual developmental disorder, autosomal recessive 71Total: 24

ALKBH8-related disorderTotal: 19

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138775.3. 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			1 clinvar	24 clinvar	1 clinvar	26
missense			113 clinvar	21 clinvar	3 clinvar	137
nonsense		5 clinvar	2 clinvar			7
start loss						0
frameshift	2 clinvar	2 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	2	8	119	45	4	178

Highest pathogenic variant AF is 0.000011492767

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138775.3	RefSeq	NP_620130.2	11	MANE Select
ENST00000428149.7	Ensembl	ENSP00000415885.2	11	MANE Select
NM_001301010.3	RefSeq	NP_001287939.2	11	Standard
NM_001378133.1	RefSeq	NP_001365062.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

tRNA modification in the nucleus and cytosol
tRNA processing
Metabolism of RNA

Biological Process

tRNA wobble uridine modification
cellular response to DNA damage stimulus
tRNA methylation
oxidation-reduction process

Molecular Function

tRNA binding
iron ion binding
protein binding
zinc ion binding
tRNA (uracil) methyltransferase activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428149
Coding exons: 11
Length: 63021
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125726
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.854	290	334	0.869	0.0000169	4363
Missense (PolyPhen)		109	131.53	0.8287		1740
Synonymous	0.708	107	117	0.917	0.00000593	1226
Loss of Function	2.90	11	27.3	0.402	0.00000129	397

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its methyltransferase domain (PubMed:20123966, PubMed:20308323). Catalyzes the last step in the formation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA (PubMed:20123966, PubMed:20308323). Has a preference for tRNA(Arg) and tRNA(Glu), and does not bind tRNA(Lys)(PubMed:20308323). Binds tRNA and catalyzes the iron and alpha-ketoglutarate dependent hydroxylation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its dioxygenase domain, giving rise to 5-(S)-methoxycarbonylhydroxymethyluridine; has a preference for tRNA(Gly) (PubMed:21285950). Required for normal survival after DNA damage (PubMed:20308323). May inhibit apoptosis and promote cell survival and angiogenesis (PubMed:19293182). {ECO:0000269|PubMed:19293182, ECO:0000269|PubMed:20123966, ECO:0000269|PubMed:20308323, ECO:0000269|PubMed:21285950}.;

Intolerance Scores

LoFtool: 0.873
RVIS EVS: 1.24
RVIS percentile EVS: 93.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.146

Gene Damage Prediction

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