RPS6KC1

Chr 1AR

ribosomal protein S6 kinase C1

Also known as: NEDSCW, RPK118, RSKL1, S6K-delta-1, S6PKh1, humS6PKh1

NCBI Gene: 26750 ENSG00000136643 UniProt: Q96S38 OMIM: 617517

This protein binds to sphingosine kinase and phosphatidylinositol 3-phosphate to transmit sphingosine-1-phosphate signaling and recruits peroxiredoxin-3 to early endosomes and mitochondria. Mutations in RPS6KC1 cause autosomal recessive developmental and epileptic encephalopathy with onset in early infancy. The gene is highly constrained against loss-of-function variants, suggesting that complete protein loss is not well tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Sphingosine kinase catalyzes the formation of sphingosine 1 phosphate, a lipid cellular messenger. The protein encoded by this gene can bind to sphingosine kinase and to phosphatidylinositol 3-phosphate, suggesting a role in sphingosine 1 phophate signaling. The encoded protein can also bind to peroxiredoxin-3 and may help transport it to mitochondria. [provided by RefSeq, Mar 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.481 OMIM phenotype

Clinical Summary— RPS6KC1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 227 VUS of 385 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.001

Z-score 4.32

OE 0.31 (0.20–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.45Z-score

OE missense 0.95 (0.88–1.02)

519 obs / 548.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.20–0.48)

0≤0.351.4

Missense OE?0.95 (0.88–1.02)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 14 / 45.4Missense obs/exp: 519 / 548.5Syn Z: 0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateRPS6KC1-related complex neurodevelopmental disorder with spasticity and hypoplasia of corpus callosumLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7036th %ile

GOF

0.6443th %ile

LOF

0.3648th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

385 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic2

VUS227

Likely Benign101

Benign27

Conflicting5

Pathogenic

Likely Pathogenic

227

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	0	1	1	0	2
VUS	9	208	8	2	227
Likely Benign	0	9	36	56	101
Benign	0	7	12	8	27
Conflicting	—				5
Total	12	227	57	66	367

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap RPS6KC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →