GPT2

Chr 16AR

glutamic--pyruvic transaminase 2

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

NCBI Gene: 84706 ENSG00000166123 UniProt: Q8TD30 OMIM: 138210

This mitochondrial alanine transaminase catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, playing a key role in gluconeogenesis and amino acid metabolism across multiple tissues including skeletal muscle, kidney, and liver. Mutations cause neurodevelopmental disorder with microcephaly and spastic paraplegia with autosomal recessive inheritance. The gene is not highly constrained against loss-of-function variants (pLI 0.0003, LOEUF 0.698).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.701 OMIM phenotype

Clinical Summary— GPT2

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Gene-Disease Validity (ClinGen)

glutamate pyruvate transaminase 2 deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 77 VUS of 148 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 2.69

OE 0.41 (0.25–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.88Z-score

OE missense 0.70 (0.63–0.78)

216 obs / 308.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.25–0.70)

0≤0.351.4

Missense OE?0.70 (0.63–0.78)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 10 / 24.3Missense obs/exp: 216 / 308.8Syn Z: 0.57

This gene — mechanism propensity

0.6937th %ile

GOF

0.4678th %ile

LOF

0.3259th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

148 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic10

VUS77

Likely Benign28

Benign9

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	3	0	0	8
Likely Pathogenic	9	1	0	0	10
VUS	1	69	6	1	77
Likely Benign	0	5	2	21	28
Benign	0	1	1	7	9
Conflicting	—				5
Total	15	79	9	29	137

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap GPT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →