GSTA2

Chr 6

glutathione S-transferase alpha 2

Also known as: GST2, GSTA2-2, GTA2, GTH2

NCBI Gene: 2939 ENSG00000244067 UniProt: P09210

Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes function in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding these enzymes are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of some drugs. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-tranferase belonging to the alpha class. The alpha class genes, located in a cluster mapped to chromosome 6, are the most abundantly expressed glutathione S-transferases in liver. In addition to metabolizing bilirubin and certain anti-cancer drugs in the liver, the alpha class of these enzymes exhibit glutathione peroxidase activity thereby protecting the cells from reactive oxygen species and the products of peroxidation. [provided by RefSeq, Jul 2008]

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

-1.5

Missense Z

1.68

LOEUF

Clinical Summary— GSTA2

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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

9 Pathogenic / Likely Pathogenic· 27 VUS of 43 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.68LOEUF

pLI 0.000

Z-score -0.05

OE 1.02 (0.63–1.68)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-1.50Z-score

OE missense 1.39 (1.22–1.58)

162 obs / 116.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE1.02 (0.63–1.68)

0≤0.351.4

Missense OE1.39 (1.22–1.58)

0≤0.61.4

Synonymous OE1.56

0≤1.21.6

LoF obs/exp: 10 / 9.8Missense obs/exp: 162 / 116.4Syn Z: -2.77

GOFDN

Badonyi & Marsh 2024 ↗

0.76top 25%

GOF

0.78top 25%

LOF

0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.