ADAT3

protein-coding

adenosine deaminase tRNA specific 3, the group of Adenosine deaminases acting on RNA

Gene summary

This gene encodes a subunit of a tRNA-specific adenosine deaminase. This heterodimeric enzyme converts adenosine to inosine in the tRNA anticodon. A mutation in this gene causes a syndrome characterized by intellectual disability and strabismus. This gene shares its 5' exon with the overlapping gene, secretory carrier membrane protein 4 (Gene ID: 113178). [provided by RefSeq, Jul 2016]

MANE transcript

NM_138422.4

Inheritance

ClinVar variants

P:6U:137B:35

Top phenotype

Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr19:1,905,399-1,913,447

External References & Databases

Ensembl (ENSG00000213638)

Transcript & Mutation Effects

hg38 • Region Span ~8.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability-strabismus syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014119

Submitter: Ambry Genetics

intellectual disability-strabismus syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014119

Submitter: ClinGen

*ADAT3* encodes the non-catalytic subunit of the heterodimeric ADAT2/ADAT3 tRNA deaminase complex, which catalyzes adenosine-to-inosine modification at position 34 of transfer RNAs, essential for accurate protein translation and decoding of C-ending codons. Biallelic loss-of-function variants in *ADAT3* cause autosomal recessive intellectual disability through deficient wobble inosine modification, leading to impaired protein synthesis that particularly affects neurodevelopment. Five different genetic variants identified so far include the highly recurrent p.Val144Met founder mutation found in over 90% of total reported patients, with 55 patients from 29 consanguineous families, predominantly from Middle Eastern countries (Alazami et al., PMID: 23620220; Del-Pozo-Rodriguez et al., PMID: 40120092), along with two missense variants (p.Ala196Val, p.Ala196Leu) (Ramos et al., PMID: 32763916; Thomas et al., PMID: 31687266), one frameshift variant (8-bp duplication causing p.Glu36Glyfs44) (Chaleshtori et al., PMID: 29796286), and one nonsense variant (p.Gln274*) (PMID: 32763916), found in homozygous and compound heterozygous states. Strong segregation evidence with maximum points awarded demonstrates co-segregation of variants with disease phenotype across multiple affected families. Clinical features consistently include intellectual disability (100%) and absent or severely delayed speech, with variable features such as microcephaly, seizures, muscle tone defects, and other features such as failure to thrive, strabismus, and dysmorphic facial features. Functional studies demonstrate that *ADAT3* variants reduce enzymatic activity, protein stability, and tRNA modification in patient cells, with rescue experiments confirming that catalytic function is essential for proper neuronal migration and cortical development. In summary, there is moderate evidence supporting the relationship between *ADAT3* and autosomal recessive intellectual disability-strabismus syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 16, 2025 (SOP Version 11).

intellectual disability-strabismus syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014119

Submitter: PanelApp Australia

intellectual disability-strabismus syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014119

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disability-strabismus syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014119

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic faciesAR

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: 23620220; 26842963; 29796286; 30296593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAT3 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 107

not providedTotal: 51

Intellectual disability-strabismus syndromeTotal: 30

not specifiedTotal: 23

ADAT3-related disorderTotal: 12

Intellectual disabilityTotal: 2

Neurodevelopmental disorder with brain abnormalitiesTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138422.4. 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				20 clinvar	2 clinvar	22
missense		2 clinvar	133 clinvar	12 clinvar	1 clinvar	148
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift	1 clinvar	3 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	1	5	137	32	3	178

Highest pathogenic variant AF is 0.0001902746

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138422.4	RefSeq	NP_612431.2	1	MANE Select
ENST00000329478.4	Ensembl	ENSP00000332448.2	1	MANE Select
NM_001329533.2	RefSeq	NP_001316462.1	1	Standard
ENST00000454697.1	Ensembl	ENSP00000404502.2	1	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 adenosine to inosine editing
tRNA processing

Molecular Function

catalytic activity
metal ion binding
tRNA-specific adenosine-34 deaminase activity

Cellular Component

nucleoplasm
tRNA-specific adenosine-34 deaminase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329478
Coding exons: 1
Length: 8068
Individuals with no LoFs: 120957
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 120980
p: 0.0000951

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.422	235	217	1.08	0.0000171	2220
Missense (PolyPhen)		48	47.518	1.0101		507
Synonymous	0.214	103	106	0.974	0.00000912	822
Loss of Function	0.803	4	6.15	0.651	2.66e-7	76

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000058	0.000056	rare
Finnish	0.00022	0.00015	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00017	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Mental retardation, autosomal recessive 36 (MRT36) [MIM:615286]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT36 is often associated with esotropia and failure to thrive. Other more variable features included microcephaly, hypotonia, and mild brain abnormalities on MRI, such as dilated ventricles or delayed myelination. {ECO:0000269|PubMed:23620220}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.854

Gene Damage Prediction

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