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: 6196ENSG00000071242UniProt: Q15349

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]

146
ClinVar variants
51
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— RPS6KA2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 85 VUS of 146 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.28 (0.18–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.60–0.73)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 13 / 46.4Missense obs/exp: 310 / 467.0Syn Z: 0.17

ClinVar Variant Classifications

146 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic3
VUS85
Likely Benign9
Benign1
48
Pathogenic
3
Likely Pathogenic
85
VUS
9
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
48
0
48
Likely Pathogenic
0
0
3
0
3
VUS
1
71
13
0
85
Likely Benign
0
4
1
4
9
Benign
0
0
0
1
1
Total175655146

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RPS6KA2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
HNF4A functions as a hepatocellular carcinoma oncogene or tumor suppressor depending upon the AMPK pathway activity status.
Qin Z et al.·Cancer Lett
2025
miR-512-3p/RPS6KA2 Axis Regulates Cisplatin Resistance in Ovarian Cancer via Autophagy and Ferroptosis.
Wu J et al.·Oncol Res
2025
Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.
Stephanou C et al.·Int J Mol Sci
2024Review
Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1.
Sung H et al.·Mol Genet Genomic Med
2020
ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2.
Pancholi S et al.·Endocr Relat Cancer
2008
Genome-wide association scan of dental caries in the permanent dentition.
Wang X et al.·BMC Oral Health
2012Meta-analysis
Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC).
Ventham NT et al.·Cell Mol Gastroenterol Hepatol
2023Cohort
Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.
Loesch DP et al.·Ann Neurol
2021
Epigenome-wide methylation differences in a group of lean and obese women - A HUNT Study.
Kvaløy K et al.·Sci Rep
2018
Exploration of functional relations among differentially co-expressed genes identifies regulators in glioblastoma.
Kumar S et al.·Comput Biol Chem
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools