GPT2

Chr 16AR

glutamic--pyruvic transaminase 2

Also known as: ALT2, GPT 2, MRT49, NEDSPM

NCBI Gene: 84706ENSG00000166123UniProt: Q8TD30

This gene encodes a mitochondrial alanine transaminase, a pyridoxal enzyme that catalyzes the reversible transamination between alanine and 2-oxoglutarate to generate pyruvate and glutamate. Alanine transaminases play roles in gluconeogenesis and amino acid metabolism in many tissues including skeletal muscle, kidney, and liver. Activating transcription factor 4 upregulates this gene under metabolic stress conditions in hepatocyte cell lines. A loss of function mutation in this gene has been associated with developmental encephalopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly and spastic paraplegiaMIM #616281
AR
160
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GPT2
🧬
Gene-Disease Validity (ClinGen)
glutamate pyruvate transaminase 2 deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 86 VUS of 160 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.000
Z-score 2.69
OE 0.41 (0.25–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.88Z-score
OE missense 0.70 (0.63–0.78)
216 obs / 308.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.41 (0.25–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.63–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 10 / 24.3Missense obs/exp: 216 / 308.8Syn Z: 0.57

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic10
VUS86
Likely Benign28
Benign9
Conflicting5
22
Pathogenic
10
Likely Pathogenic
86
VUS
28
Likely Benign
9
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
3
17
0
22
Likely Pathogenic
7
1
2
0
10
VUS
1
68
16
1
86
Likely Benign
0
5
2
21
28
Benign
0
1
1
7
9
Conflicting
—5
Total10783829160

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GPT2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly and spastic paraplegia

MIM #616281

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Screening mitochondria-related biomarkers in skin and plasma of atopic dermatitis patients by bioinformatics analysis and machine learning.
Yu H et al.·Front Immunol
2024Cohort
GPT2 mutations in autosomal recessive developmental disability: extending the clinical phenotype and population prevalence estimates.
Ouyang Q et al.·Hum Genet
2019
GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
Ponton-Almodovar A et al.·Sci Rep
2025
Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo.
Baytas O et al.·Hum Mol Genet
2022Functional
Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy.
Yao Y et al.·Cancer Immunol Immunother
2025
GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.
Hengel H et al.·Clin Genet
2018
Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.
Ouyang Q et al.·Proc Natl Acad Sci U S A
2016
Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia.
Kaymakcalan H et al.·Am J Med Genet A
2018
SPTBN1 abrogates renal clear cell carcinoma progression via glycolysis reprogramming in a GPT2-dependent manner.
Wu J et al.·J Transl Med
2022
A general practice workplace-based assessment instrument: Content and construct validity.
Fielding A et al.·Med Teach
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools