SIK1

Chr 21

salt inducible kinase 1

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

NCBI Gene: 150094 ENSG00000142178 UniProt: P57059

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 30

Clinical highlights

Gene–disease validity (ClinGen)

Limited · genetic developmental and epileptic encephalopathy · AD · ClinGen 2024

not for standalone diagnostic reporting

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.34

LOEUF· LoF intol.

GOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in SIK1?

gnomAD v4 · ~175k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 770

18 rare PASS variants

Rare truncating (LoF)

1 in 1,800

3 rare PASS variants

Rare synonymous (reference)

1 in 580

8 rare PASS variants

Rare missense and truncating variants are carried at similar rates in SIK1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 4 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~134k	1 in 690	≈ 1 in 130,000
African / African American	~9,914	1 in 1,100	none seen
East Asian	~3,821	none seen	1 in 650
Admixed American	~2,092	1 in 320	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): 0 of 13 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 5, 6 and 8 more poorly covered. Genomes: 0 of 13 (exons 2, 3, 4, 5, 6 and 8 more below).? see exons ↓