ALPK1

alpha kinase 1

Basic information

Region (hg38): 4:112285509-112442621

Links

ENSG00000073331 ∙ NCBI:80216 ∙ OMIM:607347 ∙ HGNC:20917 ∙ Uniprot:Q96QP1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (Strong), mode of inheritance: AD
• retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (Supportive), mode of inheritance: AD
• retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome	AD	Gastrointestinal	The condition can include splenomegaly and related sequelae, such as cytopenia, and splenectomy has been described as being indicated in some individuals	Gastrointestinal; Hematologic; Neurologic; Ophthalmologic	22307799; 30967659; 31939038

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALPK1 gene.

• not provided (1 variants)
• Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (1 variants)
• ALPK1-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALPK1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	109	21	132
missense	1		284	32	36	353
nonsense			7	2	1	10
start loss						0
frameshift			20	4	1	25
inframe indel			5		1	6
splice donor/acceptor (+/-2bp)			3			3
splice region			16	11	6	33
non coding			3	38	2	43
Total	1	0	324	185	62

Variants in ALPK1

This is a list of pathogenic ClinVar variants found in the ALPK1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-112377800-C-A			Uncertain significance (Sep 26, 2022)
4-112377809-T-C		Inborn genetic diseases • ALPK1-related disorder	Uncertain significance (Aug 19, 2023)
4-112377817-T-C			Uncertain significance (Dec 13, 2022)
4-112377831-G-A		ALPK1-related disorder	Benign (Aug 30, 2023)
4-112377832-G-A		Inborn genetic diseases • ALPK1-related disorder	Uncertain significance (Dec 01, 2023)
4-112377845-T-G			Uncertain significance (Dec 26, 2022)
4-112377846-G-A			Likely benign (Apr 14, 2023)
4-112377850-G-A			Uncertain significance (Aug 17, 2022)
4-112377851-C-G			Uncertain significance (Oct 03, 2023)
4-112377851-C-T			Uncertain significance (Oct 20, 2023)
4-112377852-G-A			Benign (Jan 29, 2024)
4-112377861-G-A			Likely benign (Nov 13, 2023)
4-112377863-C-T			Benign (Aug 17, 2023)
4-112377864-G-A			Likely benign (Jun 11, 2023)
4-112377864-G-C			Likely benign (Feb 15, 2023)
4-112377869-A-C			Uncertain significance (Aug 05, 2022)
4-112377876-G-T			Uncertain significance (Jan 10, 2023)
4-112377879-C-T			Likely benign (Apr 07, 2022)
4-112377880-G-A			Likely benign (Oct 13, 2023)
4-112377890-G-A			Uncertain significance (Dec 30, 2023)
4-112377914-G-A			Likely benign (Nov 28, 2022)
4-112377918-C-T			Likely benign (Sep 28, 2023)
4-112382381-A-G			Likely benign (Mar 10, 2023)
4-112382382-A-G			Likely benign (Apr 09, 2022)
4-112382406-C-A			Uncertain significance (Dec 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALPK1	protein_coding	protein_coding	ENST00000458497	14	157112

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.02e-19	0.586	125039	3	706	125748	0.00282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.282	680	660	1.03	0.0000345	8162
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0109	0.0110
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.0136	0.0134
Finnish	0.00116	0.00116
European (Non-Finnish)	0.00129	0.00127
Middle Eastern	0.0136	0.0134
South Asian	0.00233	0.00232
Other	0.00213	0.00212

dbNSFP

Source: dbNSFP

• 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

Haploinsufficiency Scores

• pHI: 0.134
• hipred: N
• hipred_score: 0.233
• ghis: 0.461

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.505

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Alpk1

Gene ontology

• Biological process: cytoplasmic pattern recognition receptor signaling pathway;protein phosphorylation;positive regulation of I-kappaB kinase/NF-kappaB signaling;innate immune response
• Cellular component: cytosol
• Molecular function: protein serine/threonine kinase activity;protein binding;ATP binding;monosaccharide binding