GNA12

Chr 7

G protein subunit alpha 12

Also known as: HG1M1, NNX3, RMP, gep

NCBI Gene: 2768 ENSG00000146535 UniProt: Q03113 OMIM: 604394

The GNA12 protein is a guanine nucleotide-binding protein that activates RhoA signaling pathways and regulates cell adhesion and migration through G protein-coupled receptor signaling. Mutations cause autosomal dominant polymicrogyria, with this highly constrained gene (pLI 0.97) being intolerant to loss-of-function variants. The condition primarily affects brain development and cortical formation.

OMIM ResearchSummary from RefSeq, UniProt

Enables G protein activity; protein phosphatase 2A binding activity; and protein phosphatase activator activity. Involved in Rho-activating G protein-coupled receptor signaling pathway; regulation of TOR signaling; and regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in lateral plasma membrane; neuron projection; and neuronal cell body. Is active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.28

Clinical Summary— GNA12

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.970

Z-score 3.05

OE 0.00 (0.00–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.09Z-score

OE missense 0.60 (0.52–0.69)

131 obs / 218.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.60 (0.52–0.69)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 0 / 10.8Missense obs/exp: 131 / 218.0Syn Z: -1.74

This gene — mechanism propensity

0.5476th %ile

GOF

0.6833th %ile

LOF

0.48top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.28

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.