RPS6KA3

Chr XXLD

ribosomal protein S6 kinase A3

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

NCBI Gene: 6197 ENSG00000177189 UniProt: P51812 OMIM: 300075

This serine/threonine kinase acts downstream of ERK signaling to regulate transcription factors, translation initiation, and cellular proliferation and survival pathways. Mutations cause Coffin-Lowry syndrome and X-linked intellectual developmental disorder, with X-linked dominant inheritance affecting both males and females but typically more severely in males. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.087), consistent with its essential role in cellular signaling pathways.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Coffin-Lowry syndromeMIM #303600

XLD

Intellectual developmental disorder, X-linked 19MIM #300844

XLD

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Coffin-Lowry syndrome · XL · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — RPS6KA3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.23 (0.19–0.29)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 0 / 34.1Missense obs/exp: 64 / 275.0Syn Z: 1.41

Background carrier burden — how many people carry a rare variant somewhere in RPS6KA3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 870

236 rare PASS variants

Rare truncating (LoF)

1 in 19,000

22 rare PASS variants

Rare synonymous (reference)

1 in 280

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RPS6KA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 1,100	1 in 15,000
South Asian	~36k	1 in 790	≈ 1 in 36,000
Remaining (unassigned)	~31k	1 in 440	none seen
European (Finnish)	~27k	1 in 1,200	≈ 1 in 11,000
Admixed American	~23k	1 in 660	≈ 1 in 21,000
African / African American	~21k	1 in 300	1 in 3,900
East Asian	~20k	1 in 1,300	none seen
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,758	1 in 550	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 22 coding exons well covered in gnomAD exomes; exons 8, 20 marginal. Genomes: all 22.? see exons ↓