RPS6KA1
Chr 1ribosomal protein S6 kinase A1
Also known as: HU-1, MAPKAPK1, MAPKAPK1A, RSK, RSK1, p90Rsk
The protein is a serine/threonine kinase that phosphorylates substrates in MAPK signaling pathways, regulates translation through ribosomal protein S6 phosphorylation, and modulates mTOR signaling to control cellular proliferation, survival, and differentiation. Mutations cause Coffin-Lowry syndrome, an X-linked disorder characterized by intellectual disability, distinctive facial features, and progressive skeletal abnormalities. The gene is highly constrained against loss-of-function variants (pLI = 0.0019, LOEUF = 0.515), consistent with its role in fundamental cellular processes.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Moderately missense-constrained (top ~2.5%)
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.
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
130 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 4 | 0 | 4 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 0 | 87 | 7 | 0 | 94 |
Likely Benign | 0 | 3 | 0 | 2 | 5 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 0 | 90 | 11 | 2 | 103 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
RPS6KA1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools