GOT2

protein-coding

glutamic-oxaloacetic transaminase 2

Gene summary

Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

MANE transcript

NM_002080.4

Inheritance

ClinVar variants

P:3U:81B:40

Top phenotype

Developmental and epileptic encephalopathy 82

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr16:58,707,131-58,734,342

External References & Databases

Ensembl (ENSG00000125166)

Transcript & Mutation Effects

hg38 • Region Span ~27.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 82STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032880

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *GOT2* and *GOT2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 27, 2025. The *GOT2* gene encodes the mitochondrial glutamate oxaloacetate transaminase, also known as aspartate aminotransferase. *GOT2* is a pyridoxal 5’-phosphate (PLP)-dependent enzyme that is part of the malate-aspartate shuttle (MAS) which plays an important role in intracellular NAD(H) redox homeostasis. The *GOT2* gene was first reported in relation to autosomal recessive *GOT2*-related primary mitochondrial disease in 2019 (PMID: 31422819). *GOT2* has been associated with a single disease entity to date; developmental and epileptic encephalopathy 82 [OMIM# 618721]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *GOT2*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 variants (eight missense, one in-frame deletion, one exon 1 duplication) identified in 10 unrelated cases from three publications (PMIDs: 31422819, 37977948, 41001736). Clinical features in affected individuals include global developmental delay, spastic quadriplegia, absent speech or very limited verbal communication, severe to profound intellectual disability, acquired microcephaly, infantile onset seizures, feeding difficulties, and frequent infection. Variable brain MRI abnormalities have been reported in all affected individuals to date including cerebral atrophy and corpus callosum hypoplasia. Consistent metabolic abnormalities include elevated serum lactate and ammonia levels. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration in patient cells (PMID: 31422819), and mouse and zebrafish models (PMID: 31422819). In summary, there is moderate evidence to support the relationship between *GOT2* and autosomal recessive *GOT2*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 27, 2025 (SOP Version 11).

developmental and epileptic encephalopathy, 82LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032880

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 82STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032880

Submitter: G2P

developmental and epileptic encephalopathy, 82STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032880

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 82AR

Manifestation: Biochemical; Neurologic

Intervention: Neurologic

Rationale: The condition can involve early-onset metabolic encephalopathy, and treatment with combined pyridoxine and serine has been described asresulting in improvement in seizures and mild developmental progress

Refs: 31422819

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GOT2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 100

not specifiedTotal: 50

Developmental and epileptic encephalopathy, 82Total: 13

GOT2-related disorderTotal: 5

Developmental and epileptic encephalopathyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002080.4. 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			1 clinvar	27 clinvar	5 clinvar	33
missense		3 clinvar	76 clinvar	5 clinvar	3 clinvar	87
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	3	81	32	8	124

Highest pathogenic variant AF is 0.000006864624

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002080.4	RefSeq	NP_002071.2	10	MANE Select
ENST00000245206.10	Ensembl	ENSP00000245206.5	10	MANE Select
NM_001286220.2	RefSeq	NP_001273149.1	9	Standard
ENST00000434819.2	Ensembl	ENSP00000394100.2	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Arginine and proline metabolism - Homo sapiens (human)
Phenylalanine metabolism - Homo sapiens (human)
Fat digestion and absorption - Homo sapiens (human)
Phenylalanine, tyrosine and tryptophan biosynthesis - Homo sapiens (human)

Biological Process

gluconeogenesis
2-oxoglutarate metabolic process
oxaloacetate metabolic process
aspartate metabolic process
aspartate biosynthetic process

Molecular Function

RNA binding
L-aspartate:2-oxoglutarate aminotransferase activity
phospholipid binding
kynurenine-oxoglutarate transaminase activity
amino acid binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial matrix
plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245206
Coding exons: 10
Length: 27227
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125746
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	190	252	0.754	0.0000144	2808
Missense (PolyPhen)		41	70.613	0.58063		846
Synonymous	1.93	68	91.5	0.743	0.00000523	846
Loss of Function	2.84	7	21.1	0.332	9.78e-7	243

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000085	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the irreversible transamination of the L- tryptophan metabolite L-kynurenine to form kynurenic acid (KA). Plays a key role in amino acid metabolism. Important for metabolite exchange between mitochondria and cytosol. Facilitates cellular uptake of long-chain free fatty acids. {ECO:0000269|PubMed:9537447}.;

Recessive Scores

pRec: 0.975

Intolerance Scores

LoFtool: 0.107
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.370

Gene Damage Prediction

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