Glutamate pyruvate transaminase 2 deficiency

Summary

Glutamate pyruvate transaminase 2 deficiency (MONDO:0014567) is a disease caused by GPT2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GPT2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 37
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	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:0000252	Microcephaly	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000601	Hypotelorism	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006829	Severe muscular hypotonia	Frequent (30-79%)
HP:0011470	Nasogastric tube feeding in infancy	Frequent (30-79%)
HP:0000341	Narrow forehead	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0011400	Abnormal CNS myelination	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glutamate pyruvate transaminase 2 deficiency
Mondo ID	MONDO:0014567
OMIM	616281
Orphanet	477673
DOID	DOID:0070542
UMLS	C4225388
MedGen	906606
GARD	0017853
NORD	91168
Is cancer (heuristic)	no

Also known as: glutamate pyruvate transaminase 2 deficiency · GPT2 Deficiency · GPT2 deficiency · mental retardation, autosomal recessive 49 · mental retardation, autosomal recessive type 49 · neurodevelopmental disorder with microcephaly and spastic paraplegia · postnatal microcephaly-infantile hypotonia-spastic diplegia-dysarthria-intellectual disability syndrome

Data availability: 37 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › glutamate pyruvate transaminase 2 deficiency

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

37 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 7 pathogenic, 6 likely pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324512	NM_133443.4(GPT2):c.274C>T (p.Arg92Ter)	GPT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254655	NM_133443.4(GPT2):c.1210C>T (p.Arg404Ter)	GPT2	Pathogenic	criteria provided, single submitter
3069205	NM_133443.4(GPT2):c.306del (p.Gln103fs)	GPT2	Pathogenic	criteria provided, single submitter
4057298	NM_133443.4(GPT2):c.22_35del (p.Val8fs)	GPT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522105	NM_133443.4(GPT2):c.70C>T (p.Gln24Ter)	GPT2	Pathogenic	criteria provided, single submitter
983537	NM_133443.4(GPT2):c.400C>T (p.Arg134Cys)	GPT2	Pathogenic	no assertion criteria provided
983538	NM_133443.4(GPT2):c.1435G>A (p.Val479Met)	GPT2	Pathogenic	no assertion criteria provided
983539	NM_133443.4(GPT2):c.1432_1433del (p.Val478fs)	GPT2	Pathogenic	no assertion criteria provided
983541	NM_133443.4(GPT2):c.812A>C (p.Asn271Thr)	GPT2	Pathogenic	no assertion criteria provided
187856	NM_133443.4(GPT2):c.459C>G (p.Ser153Arg)	GPT2	Likely pathogenic	criteria provided, single submitter
2572428	NM_133443.4(GPT2):c.58del (p.Trp20fs)	GPT2	Likely pathogenic	criteria provided, single submitter
2572609	NM_133443.4(GPT2):c.333+2T>G	GPT2	Likely pathogenic	criteria provided, single submitter
2572611	NM_133443.4(GPT2):c.924_925del (p.Pro309fs)	GPT2	Likely pathogenic	criteria provided, single submitter
3893149	NM_133443.4(GPT2):c.643C>T (p.Gln215Ter)	GPT2	Likely pathogenic	criteria provided, single submitter
988735	NM_133443.4(GPT2):c.1177dup (p.Val393fs)	GPT2	Likely pathogenic	no assertion criteria provided
1701973	NM_133443.4(GPT2):c.1441G>A (p.Gly481Ser)	GPT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
72070	NM_133443.4(GPT2):c.1172C>T (p.Pro391Leu)	GPT2	Conflicting classifications of pathogenicity	no assertion criteria provided
1031115	NM_133443.4(GPT2):c.589A>G (p.Ile197Val)	GPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031604	NM_133443.4(GPT2):c.371G>C (p.Ser124Thr)	GPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031605	NM_133443.4(GPT2):c.478C>T (p.Arg160Cys)	GPT2	Uncertain significance	criteria provided, single submitter
1303628	NM_133443.4(GPT2):c.487G>A (p.Val163Met)	GPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1706442	NM_133443.4(GPT2):c.1035C>T (p.Gly345=)	GPT2	Uncertain significance	criteria provided, single submitter
1805209	NM_133443.4(GPT2):c.328C>T (p.Arg110Trp)	GPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805242	NM_133443.4(GPT2):c.886C>T (p.Leu296Phe)	GPT2	Uncertain significance	criteria provided, single submitter
1805491	NM_133443.4(GPT2):c.1481+3del	GPT2	Uncertain significance	criteria provided, single submitter
1805495	NM_133443.4(GPT2):c.839A>G (p.Lys280Arg)	GPT2	Uncertain significance	criteria provided, single submitter
2455852	NM_133443.4(GPT2):c.545A>T (p.Tyr182Phe)	GPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
254656	NM_133443.4(GPT2):c.815C>T (p.Pro272Leu)	GPT2	Uncertain significance	criteria provided, single submitter
2585589	NM_133443.4(GPT2):c.1120C>T (p.Arg374Cys)	GPT2	Uncertain significance	criteria provided, single submitter
2921252	NM_133443.4(GPT2):c.217G>A (p.Gly73Ser)	GPT2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
GPT2	Definitive	Autosomal recessive	glutamate pyruvate transaminase 2 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPT2	Orphanet:477673	Postnatal microcephaly-infantile hypotonia-spastic diplegia-dysarthria-intellectual disability syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GPT2	HGNC:18062	ENSG00000166123	Q8TD30	Alanine aminotransferase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GPT2	Alanine aminotransferase 2	Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GPT2	Other/Unknown	no		Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GPT2	237	ubiquitous	marker	lower esophagus mucosa, body of pancreas, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPT2	2,823

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPT2	Q8TD30	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alanine metabolism	1	5710.0×	2e-04	GPT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-alanine metabolic process	1	16852.0×	2e-04	GPT2
L-alanine catabolic process	1	4213.0×	4e-04	GPT2
2-oxoglutarate metabolic process	1	936.2×	0.001	GPT2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GPT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GPT2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GPT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.