RPS6KA2

Chr 6

ribosomal protein S6 kinase A2

Also known as: HU-2, MAPKAPK1C, RSK, RSK3, S6K-alpha, S6K-alpha2, p90-RSK3, p90RSK2

NCBI Gene: 6196 ENSG00000071242 UniProt: Q15349 OMIM: 601685

The protein is a serine/threonine kinase that acts downstream of ERK signaling to regulate transcription factors, translation, and cellular proliferation, survival, and differentiation. Mutations cause Coffin-Lowry syndrome, an X-linked intellectual disability disorder characterized by distinctive facial features, skeletal abnormalities, and progressive intellectual disability that primarily affects males. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternative splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.45

Clinical Summary— RPS6KA2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.009

Z-score 4.55

OE 0.28 (0.18–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.58Z-score

OE missense 0.66 (0.60–0.73)

310 obs / 467.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.28 (0.18–0.45)

0≤0.351.4

Missense OE?0.66 (0.60–0.73)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 13 / 46.4Missense obs/exp: 310 / 467.0Syn Z: 0.17

This gene — mechanism propensity

0.76top 25%

GOF

0.6444th %ile

LOF

0.3356th %ile

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

DNprediction above median

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.