RPS6KA3

Chr XXLD

ribosomal protein S6 kinase A3

Also known as: CLS, HU-3, ISPK-1, MAPKAPK1B, MRX19, RSK, RSK2, S6K-alpha3

NCBI Gene: 6197ENSG00000177189UniProt: P51812

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 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. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Coffin-Lowry syndromeMIM #303600
XLD
Intellectual developmental disorder, X-linked 19MIM #300844
XLD
465
ClinVar variants
155
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— RPS6KA3
🧬
Gene-Disease Validity (ClinGen)
Coffin-Lowry syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
155 Pathogenic / Likely Pathogenic· 123 VUS of 465 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.09LOEUF
pLI 1.000
Z-score 5.41
OE 0.00 (0.00–0.09)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
4.52Z-score
OE missense 0.23 (0.19–0.29)
64 obs / 275.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.00 (0.00–0.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.23 (0.19–0.29)
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.0.81
0≤1.21.6
LoF obs/exp: 0 / 34.1Missense obs/exp: 64 / 275.0Syn Z: 1.41

ClinVar Variant Classifications

465 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic119
Likely Pathogenic36
VUS123
Likely Benign127
Benign50
Conflicting10
119
Pathogenic
36
Likely Pathogenic
123
VUS
127
Likely Benign
50
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
30
10
78
1
119
Likely Pathogenic
13
14
9
0
36
VUS
3
89
29
2
123
Likely Benign
0
5
72
50
127
Benign
0
1
35
14
50
Conflicting
—10
Total4611922367465

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

View in ClinVar →

Protein Context — Lollipop Plot

RPS6KA3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RPS6KA3-related Coffin-Lowry syndrome

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersSkin
G2P ↗
frameshift variantstop gainedmissense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Coffin-Lowry syndrome

MIM #303600

Molecular basis of disorder known

X-linked dominant

Intellectual developmental disorder, X-linked 19

MIM #300844

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — RPS6KA3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Coffin-Lowry syndrome: a systematic review of RPS6KA3 confirmed cases and implications for diagnosis and counseling.
Maity S et al.·Front Genet
2025🔓 Open AccessReview
Stimulation of insulin secretion induced by low 4-cresol dose involves the RPS6KA3 signalling pathway.
Brial F et al.·PLoS One
2024🔓 Open Access
A 6-year-old boy with an atypical liver neoplasm harboring a novel RPS6KA3 variant.
Bustamante D et al.·Lab Med
2024
Establishment of linkage phase, using Oxford Nanopore Technologies, for preimplantation genetic testing of Coffin-Lowry syndrome with a de novo RPS6KA3 mutation.
Wen X et al.·Front Genet
2023🔓 Open Access
A short peptide LINC00665_18aa encoded by lncRNA LINC00665 suppresses the proliferation and migration of osteosarcoma cells through the regulation of the CREB1/RPS6KA3 interaction.
Pan J et al.·PLoS One
2023🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools