RPS6KA4

Chr 11

ribosomal protein S6 kinase A4

Also known as: MSK2, RSK-B, S6K-alpha-4

NCBI Gene: 8986 ENSG00000162302 UniProt: O75676

The protein is a serine/threonine kinase that phosphorylates transcription factors CREB1 and ATF1, histone H3, and other substrates to regulate gene expression, particularly inflammatory genes and immediate early genes. Mutations cause neurodevelopmental disorders with intellectual disability, speech delay, and behavioral abnormalities, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.997), indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, 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 CREB1 and ATF1. The encoded protein can also phosphorylate histone H3 to regulate certain inflammatory genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.27

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.27LOEUF

pLI 0.997

Z-score 5.07

OE 0.13 (0.07–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.70Z-score

OE missense 0.55 (0.50–0.60)

290 obs / 529.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.27)

0≤0.351.4

Missense OE?0.55 (0.50–0.60)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 5 / 39.3Missense obs/exp: 290 / 529.3Syn Z: 1.97

Background carrier burden — how many people carry a rare variant somewhere in RPS6KA4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 85

931 rare PASS variants

Rare truncating (LoF)

1 in 2,500

97 rare PASS variants

Rare synonymous (reference)

1 in 120

528 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RPS6KA4. 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)	~556k	1 in 110	1 in 3,300
South Asian	~43k	1 in 100	1 in 1,800
Remaining (unassigned)	~30k	1 in 68	1 in 730
European (Finnish)	~27k	1 in 230	1 in 2,000
Admixed American	~22k	1 in 49	1 in 980
African / African American	~21k	1 in 92	1 in 1,300
East Asian	~20k	1 in 82	1 in 640
Ashkenazi Jewish	~13k	1 in 170	1 in 880
Middle Eastern	~2,884	1 in 64	≈ 1 in 2,900

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): 15 of 17 coding exons well covered in gnomAD exomes; exons 1, 17 marginal. Genomes: all 17.? see exons ↓