SIK1

Chr 21AD

salt inducible kinase 1

Also known as: DEE30, MSK, SIK, SIK-1, SIK1B, SNF1LK

NCBI Gene: 150094 ENSG00000142178 UniProt: P57059 OMIM: 605705

The protein is a serine/threonine kinase containing a ubiquitin-associated domain and functions as a member of the AMPK subfamily involved in cellular signal transduction pathways. Mutations cause developmental and epileptic encephalopathy 30, which follows an autosomal dominant inheritance pattern. The high pLI score (0.94) and low LOEUF score (0.34) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely mechanism of pathogenicity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.341 OMIM phenotype

Clinical Summary— SIK1

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 500 VUS of 1113 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.937

Z-score 4.31

OE 0.16 (0.08–0.34)

Highly constrained

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

Missense Constraint?

1.49Z-score

OE missense 0.80 (0.74–0.88)

365 obs / 454.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.08–0.34)

0≤0.351.4

Missense OE?0.80 (0.74–0.88)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 5 / 30.8Missense obs/exp: 365 / 454.3Syn Z: 0.08

ClinVar Variant Classifications

1113 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic4

VUS500

Likely Benign488

Benign54

Conflicting54

Pathogenic

Likely Pathogenic

500

VUS

488

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	4	0	0	0	4
VUS	23	442	31	4	500
Likely Benign	3	55	150	280	488
Benign	0	12	31	11	54
Conflicting	—				54
Total	32	511	212	295	1,104

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

View in ClinVar →

90 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap SIK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →