GABA aminotransaminase deficiency

Summary

GABA aminotransaminase deficiency (MONDO:0013166) is a disease caused by ABAT (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABAT (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 770
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0200134	Epileptic encephalopathy	Obligate (100%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0007266	Cerebral dysmyelination	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0032531	Elevated CSF gamma-aminobutyric acid concentration	Very frequent (80-99%)
HP:0410053	Elevated circulating gamma-aminobutyric acid concentration	Very frequent (80-99%)
HP:0500253	Increased level of gamma-aminobutyric acid in urine	Very frequent (80-99%)
HP:0000098	Tall stature	Frequent (30-79%)
HP:0000845	Elevated circulating growth hormone concentration	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0007272	Progressive psychomotor deterioration	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0025430	High-pitched cry	Frequent (30-79%)
HP:0100786	Hypersomnia	Frequent (30-79%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	GABA aminotransaminase deficiency
Mondo ID	MONDO:0013166
MeSH	C535407
OMIM	613163
Orphanet	2066
DOID	DOID:0060174
SNOMED CT	237941007
UMLS	C0342708
MedGen	137977
GARD	0000194
Is cancer (heuristic)	no

Also known as: 4 alpha aminobutyrate transaminase deficiency · ABAT · GABA aminotransferase deficiency · GABA transaminase deficiency · GABAT · gamma aminobutyrate transaminase deficiency · gamma aminobutyric acid transaminase deficiency · gamma-aminobutyric acid transaminase deficiency

Data availability: 770 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › gamma-amino butyric acid metabolism disorder › GABA aminotransaminase deficiency

Related subtypes (2): homocarnosinosis, succinic semialdehyde dehydrogenase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

262 likely benign, 207 uncertain significance, 58 benign, 23 conflicting classifications of pathogenicity, 21 likely pathogenic, 16 pathogenic, 7 benign/likely benign, 4 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
162034	NM_020686.6(ABAT):c.631C>T (p.Leu211Phe)	ABAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162035	NM_020686.6(ABAT):c.1433T>C (p.Leu478Pro)	ABAT	Pathogenic	criteria provided, single submitter
162036	NM_020686.6(ABAT):c.275G>A (p.Arg92Gln)	ABAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162037	NM_000663.4(ABAT):c.199-?_316+?del	ABAT	Pathogenic	criteria provided, single submitter
16216	NM_020686.6(ABAT):c.659G>A (p.Arg220Lys)	ABAT	Pathogenic	criteria provided, single submitter
16217	ABAT, 3-PRIME DELETION	ABAT	Pathogenic	no assertion criteria provided
2004622	NM_020686.6(ABAT):c.1128C>G (p.Tyr376Ter)	ABAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2011985	NM_020686.6(ABAT):c.378dup (p.Asn127fs)	ABAT	Pathogenic	criteria provided, single submitter
2012439	NM_020686.6(ABAT):c.274C>T (p.Arg92Ter)	ABAT	Pathogenic	criteria provided, single submitter
2131506	NM_020686.6(ABAT):c.829_832del (p.Leu276_Ile277insTer)	ABAT	Pathogenic	criteria provided, single submitter
2426571	NC_000016.9:g.(?8839838)(8870367_?)del	ABAT	Pathogenic	criteria provided, single submitter
2674702	NM_020686.6(ABAT):c.22C>T (p.Gln8Ter)	ABAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339972	NC_000016.9:g.(?8768473)(8878428_?)del	ABAT	Pathogenic	criteria provided, single submitter
3376949	NM_020686.6(ABAT):c.1031G>A (p.Trp344Ter)	ABAT	Pathogenic	criteria provided, single submitter
3659859	NM_020686.6(ABAT):c.658_659del (p.Arg220fs)	ABAT	Pathogenic	criteria provided, single submitter
438385	NM_000663.5:c.199_316del	ABAT	Pathogenic	no assertion criteria provided
438386	NM_020686.6(ABAT):c.817-2A>G	ABAT	Pathogenic	no assertion criteria provided
438387	NM_020686.6(ABAT):c.1460T>C (p.Leu487Pro)	ABAT	Pathogenic	no assertion criteria provided
4713129	NM_020686.6(ABAT):c.1145G>A (p.Trp382Ter)	ABAT	Pathogenic	criteria provided, single submitter
3243341	NC_000016.9:g.(?8829597)(8941682_?)del	PMM2	Pathogenic	criteria provided, single submitter
1067743	NM_020686.6(ABAT):c.1123-1G>A	ABAT	Likely pathogenic	criteria provided, single submitter
1473431	NM_020686.6(ABAT):c.169-2A>G	ABAT	Likely pathogenic	criteria provided, single submitter
1507444	NM_020686.6(ABAT):c.603+1G>A	ABAT	Likely pathogenic	criteria provided, single submitter
1522891	NC_000016.9:g.(?8844259)(8875287_?)del	ABAT	Likely pathogenic	criteria provided, single submitter
1522940	NC_000016.9:g.(?8851594)(8862850_?)dup	ABAT	Likely pathogenic	criteria provided, single submitter
1698381	NM_020686.6:c.(168+1_169-1)_(366+1_367-1)del	ABAT	Likely pathogenic	criteria provided, single submitter
2070793	NM_020686.6(ABAT):c.199-2A>C	ABAT	Likely pathogenic	criteria provided, single submitter
2139428	NM_020686.6(ABAT):c.317-2A>G	ABAT	Likely pathogenic	criteria provided, single submitter
2506561	GRCh37/hg19 16p13.2(chr16:8841965-8851663)	ABAT	Likely pathogenic	criteria provided, single submitter
2674703	NM_020686.6(ABAT):c.4dup (p.Ala2fs)	ABAT	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABAT	Definitive	Autosomal recessive	GABA aminotransaminase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABAT	Orphanet:2066	Gamma-aminobutyric acid transaminase deficiency
PMM2	Orphanet:79318	PMM2-CDG

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABAT	HGNC:23	ENSG00000183044	P80404	4-aminobutyrate aminotransferase, mitochondrial	gencc,clinvar
CARHSP1	HGNC:17150	ENSG00000153048	Q9Y2V2	Calcium-regulated heat-stable protein 1	clinvar
TMEM186	HGNC:24530	ENSG00000184857	Q96B77	Transmembrane protein 186	clinvar
PMM2	HGNC:9115	ENSG00000140650	O15305	Phosphomannomutase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABAT	4-aminobutyrate aminotransferase, mitochondrial	Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively.
CARHSP1	Calcium-regulated heat-stable protein 1	Binds mRNA and regulates the stability of target mRNA.
TMEM186	Transmembrane protein 186	As part of the MCIA complex, required for efficient assembly of the mitochondrial complex I.
PMM2	Phosphomannomutase 2	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABAT	Enzyme (other)	yes	2.6.1.19	4NH2But_aminotransferase_euk, Aminotrans_3, PyrdxlP-dep_Trfase_major
CARHSP1	Other/Unknown	no		CSP_DNA-bd, CSD, NA-bd_OB-fold
TMEM186	Other/Unknown	no		Tmem186, TMEM70/TMEM186/TMEM223
PMM2	Enzyme (other)	yes	5.4.2.8	PMM, HAD-SF_hydro_IIB, HAD_sf

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
ganglionic eminence	1
left testis	1
right testis	1
cervix squamous epithelium	1
mucosa of transverse colon	1
tongue squamous epithelium	1
body of pancreas	1
calcaneal tendon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABAT	289	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
CARHSP1	282	ubiquitous	marker	right testis, left testis, ganglionic eminence
TMEM186	278	ubiquitous	marker	cervix squamous epithelium, mucosa of transverse colon, tongue squamous epithelium
PMM2	139	ubiquitous	marker	body of pancreas, calcaneal tendon, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMM2	2,002
CARHSP1	1,875
ABAT	1,711
TMEM186	957

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PMM2	O15305	7
CARHSP1	Q9Y2V2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABAT	P80404	93.91
TMEM186	Q96B77	60.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective PMM2 causes PMM2-CDG	1	3806.7×	0.001	PMM2
Degradation of GABA	1	1903.3×	0.001	ABAT
Synthesis of GDP-mannose	1	634.4×	0.003	PMM2
Complex I biogenesis	1	55.2×	0.023	TMEM186
Respiratory electron transport	1	31.7×	0.031	TMEM186

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
copulation	1	2106.5×	0.002	ABAT
obsolete GABA metabolic process	1	2106.5×	0.002	ABAT
GABA catabolic process	1	2106.5×	0.002	ABAT
negative regulation of gamma-aminobutyric acid secretion	1	2106.5×	0.002	ABAT
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	2106.5×	0.002	PMM2
positive regulation of prolactin secretion	1	2106.5×	0.002	ABAT
positive regulation of aspartate secretion	1	2106.5×	0.002	ABAT
obsolete GDP-mannose biosynthetic process from mannose	1	1404.3×	0.003	PMM2
negative regulation of dopamine secretion	1	1053.2×	0.003	ABAT
positive regulation of dopamine metabolic process	1	1053.2×	0.003	ABAT
positive regulation of heat generation	1	842.6×	0.004	ABAT
GDP-mannose biosynthetic process	1	702.2×	0.004	PMM2
positive regulation of inhibitory postsynaptic potential	1	702.2×	0.004	ABAT
mannose metabolic process	1	526.6×	0.004	PMM2
GABA biosynthetic process	1	526.6×	0.004	ABAT
positive regulation of uterine smooth muscle contraction	1	526.6×	0.004	ABAT
nervous system process	1	300.9×	0.006	ABAT
response to iron ion	1	234.1×	0.008	ABAT
exploration behavior	1	162.0×	0.010	ABAT
negative regulation of blood pressure	1	162.0×	0.010	ABAT
response to cocaine	1	145.3×	0.011	ABAT
response to nicotine	1	105.3×	0.013	ABAT
regulation of mRNA stability	1	105.3×	0.013	CARHSP1
mitochondrial respiratory chain complex I assembly	1	102.8×	0.013	TMEM186
cerebellum development	1	89.6×	0.015	ABAT
glycoprotein biosynthetic process	1	84.3×	0.015	PMM2
protein N-linked glycosylation	1	65.8×	0.018	PMM2
positive regulation of insulin secretion	1	63.8×	0.018	ABAT
locomotory behavior	1	44.8×	0.025	ABAT
response to ethanol	1	36.6×	0.030	ABAT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMM2	1	3
ABAT	0	0
CARHSP1	0	0
TMEM186	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBSELEN	3	PMM2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ABAT	41	Binding:41
PMM2	3	Binding:3
CARHSP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABAT	2.6.1.19	4-aminobutyrate-2-oxoglutarate transaminase
PMM2	5.4.2.8	phosphomannomutase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
EBSELEN	3	PMM2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	PMM2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ABAT
E	Difficult family or no structure, no drug	2	CARHSP1, TMEM186

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ABAT	41	—
CARHSP1	1	—
TMEM186	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.