GPS2

Chr 17

G protein pathway suppressor 2

Also known as: AMF-1

NCBI Gene: 2874 ENSG00000132522 UniProt: Q13227 OMIM: 601935

GPS2 encodes a key regulator of inflammation, lipid metabolism and mitochondrial homeostasis that acts by inhibiting the ubiquitin-conjugating enzyme UBE2N/Ubc13 and functions as both a transcriptional coactivator and corepressor depending on cellular context. Mutations cause autosomal recessive intellectual disability with microcephaly, seizures, and growth retardation. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.583), suggesting some tolerance to functional disruption.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.58

Clinical Summary— GPS2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.053

Z-score 2.94

OE 0.30 (0.16–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.16Z-score

OE missense 0.76 (0.66–0.87)

136 obs / 179.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.16–0.58)

0≤0.351.4

Missense OE?0.76 (0.66–0.87)

0≤0.61.4

Synonymous OE?1.71

0≤1.21.6

LoF obs/exp: 6 / 20.3Missense obs/exp: 136 / 179.7Syn Z: -4.48

This gene — mechanism propensity

0.6453th %ile

GOF

0.3689th %ile

LOF

0.4726th %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.