ALPK1
protein-codingalpha kinase 1
Gene summary
This gene encodes an alpha kinase. Mice which were homozygous for disrupted copies of this gene exhibited coordination defects (PMID: 21208416). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~157.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013999
Submitter: ClinGen
ALPK1 was first implicated in autosomal dominant monogenic disease in a report of 5 families all with retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headaches in 2019 (Williams et al, PMID:30967659). The same heterozygous variant in ALPK1 (c.710C>T, [p.Thr237Met]) was identified in all 5 families. This report was extended to 13 families, one with a second deleterious variant p.Tyr254Cys in a second report, highlighting more of the inflammatory features of the disease in 2022 (Kozycki et al, PMID: 35868845). Individuals with ROSAH syndrome have been found to have a variety of symptoms including ocular findings (optic disk elevation, uveitis, retinal vasculitis and retinal degeneration), inflammatory arthritis, splenomegaly, gastrointestinal inflammation, cytopenias, headaches, malaise, dental anomalies (carries and enamel defects) – potentially driven by hyposalivation, anhidrosis, and inability to lactate (Kozycki et al, PMID: 35868845). Variants in this gene have been reported in at least 15 probands in 3 publications (PMIDs: 35868845, 30967659, 36543582). Variants in this gene segregated with disease in 17 additional family members, which have been included in this curation. The gene disease relationship is supported by experimental evidence. The mechanism of pathogenicity is reported to be gain of function. Studies in primary samples and in vitro assays with mutated ALPK1 constructs lead to increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation and have elevated serum levels of CXCL1, CXCL10 and CCL2 (Kozycki et al, PMID: 35868845). In summary, there is strong evidence supporting the relationship between ALPK1 and autosomal dominant ROSAH. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Autoinflammatory GCEP on the meeting date 01/09/2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal; Hematologic; Neurologic; Ophthalmologic
Intervention: Gastrointestinal
Rationale: The condition can include splenomegaly and related sequelae, such as cytopenia, and splenectomy has been described as being indicated in some individuals
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ALPK1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025144.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 175 | 14 | 193 | ||
| missense | 2 | 1 | 476 | 79 | 19 | 577 |
| nonsense | 17 | 2 | 1 | 20 | ||
| start loss | 0 | |||||
| frameshift | 35 | 5 | 1 | 41 | ||
| splice donor/acceptor (+/-2bp) | 10 | 10 | ||||
| Total | 2 | 1 | 542 | 261 | 35 | 841 |
Highest pathogenic variant AF is 6.842969e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079420.3 | 14 | MANE Select | |
| Ensembl | ENSP00000498374.1 | 14 | MANE Select | |
| RefSeq | NP_001095876.1 | 14 | Standard | |
| RefSeq | NP_001240813.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cytoplasmic pattern recognition receptor signaling pathway
- protein phosphorylation
- positive regulation of I-kappaB kinase/NF-kappaB signaling
- innate immune response
Molecular Function
- protein serine/threonine kinase activity
- protein binding
- ATP binding
- monosaccharide binding
Cellular Component
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000458497
- Coding exons
- 14
- Length
- 157112
- Individuals with no LoFs
- 125039
- Homozygous LoFs
- 3
- Heterozygous LoFs
- 706
- Defined
- 125748
- p
- 0.00282
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.282 | 680 | 660 | 1.03 | 0.0000345 | 8162 |
| Missense (PolyPhen) | 188 | 192.66 | 0.9758 | 2431 | ||
| Synonymous | 0.467 | 254 | 264 | 0.963 | 0.0000156 | 2369 |
| Loss of Function | 1.98 | 38 | 53.6 | 0.709 | 0.00000258 | 656 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0093 | 0.0093 | notable |
| Latino/Admixed American | 0.0017 | 0.0016 | notable |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.014 | 0.013 | notable |
| Finnish | 0.0012 | 0.0012 | notable |
| European (Non-Finnish) | 0.0013 | 0.0013 | notable |
| South Asian | 0.0023 | 0.0023 | notable |
| Other | 0.0021 | 0.0021 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine/threonine-protein kinase that detects bacterial pathogen-associated molecular pattern metabolites (PAMPs) and initiates an innate immune response, a critical step for pathogen elimination and engagement of adaptive immunity (PubMed:28877472, PubMed:28222186, PubMed:30111836). Specifically recognizes and binds ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria (PubMed:30111836). ADP-Heptose-binding stimulates its kinase activity to phosphorylate and activate TIFA, triggering proinflammatory NF-kappa-B signaling (PubMed:30111836). May be involved in monosodium urate monohydrate (MSU)-induced inflammation by mediating phosphorylation of unconventional myosin MYO9A (PubMed:27169898). May also play a role in apical protein transport by mediating phosphorylation of unconventional myosin MYO1A (PubMed:15883161). {ECO:0000269|PubMed:15883161, ECO:0000269|PubMed:27169898, ECO:0000269|PubMed:28222186, ECO:0000269|PubMed:28877472, ECO:0000269|PubMed:30111836}.;
Recessive Scores
- pRec
- 0.0958
Intolerance Scores
- LoFtool
- 0.955
- RVIS EVS
- 1.46
- RVIS percentile EVS
- 95.18
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.505
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |