PHKA1

protein-coding

phosphorylase kinase regulatory subunit alpha 1, the group of Phosphorylase kinase subunits

Gene summary

Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the skeletal muscle isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

Previous symbols:

PHKA

MANE transcript

NM_002637.4

Inheritance

XL, AR

ClinVar variants

P:57U:530B:167

Top phenotype

Glycogen storage disease, type IXd

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chrX:72,578,814-72,714,319

External References & Databases

Ensembl (ENSG00000067177)

Transcript & Mutation Effects

hg38 • Region Span ~135.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease IXdDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010362

Submitter: ClinGen

*PHKA1was* first reported in relation to X-linked recessive Glycogen storage disease type IX d (GSD IXd) in 1994 (Wehner et al., PMID: 7874115). GSD IXd (OMIM:311870) is caused by a defect in the PHKA1 gene, which encodes the alpha subunit of phosphorylase kinase (PhK) in muscle. A defect in this subunit leads to reduced PhK enzyme activity. This enzyme deficiency impairs the breakdown of glycogen, resulting in its accumulation in muscle cells. Symptoms of GSD IXd commonly include muscle weakness, exercise intolerance, cramps, and, in some cases, progressive myopathy. At least 14 variants (e.g. missense, nonsense, and frameshift) have been reported in humans. Clinical evidence supporting this gene-disease relationship includes case-level data. Variants in this gene have been reported in at least 15 probands in 14 publications (PMID: 7874115, 12825073, 15637709, 22238410, 18401027, 34615823, 9731190, 35957617, 32303402, 28600779, 20080404, 35710611, 33799212, 38586167). There is no more prevalent in any ethnic group with PHKA1 gene mutation This gene-disease relationship is also supported by experimental evidence, including animal models, expression studies, biochemical function analysis. (PMID: 6020474, 8298647, 13402896, 25613900, 32707033, 33961781, 38548794, 1409665). The I strain of mice is characterized by significantly higher muscle glycogen levels compared to other strains. Studies have shown that these mice maintain elevated muscle glycogen concentrations in both fed and fasted states, regardless of dietary fat content. Notably, the I strain exhibits a deficiency in phosphorylase kinase (PhK) activity. A cross-mating study between I-strain and C57-strain mice demonstrated that the inheritance pattern is X-linked. This PhK deficiency in I-strain mice is caused by frameshift mutations in the PHKA1 gene, which encodes the alpha subunit of PhK. Protein interaction studies suggest that the alpha subunit may bind to calmodulin and the delta subunit of PhK, and also interacts with the beta and gamma subunits, contributing to the enzyme's regulatory functions. Farnesylation of the alpha subunit of phosphorylase kinase is critical for maintaining the enzyme's structural integrity. In summary, there is definitive evidence supporting the relationship between *PHKA1* and X-linked recessive Glycogen storage disease type IX d. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [January 10, 2025] (SOP Version 10).

glycogen storage disease IXdSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010362

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease IXdSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010362

Submitter: Orphanet

glycogen storage disease IXdSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010362

Submitter: Genomics England PanelApp

glycogen storage disease IXdSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010362

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Glycogen storage disease, type IXdXL

Manifestation: Biochemical; Musculoskeletal; Renal

Intervention: Pharmacogenomic; Musculoskeletal; Renal

Rationale: Individuals should avoid circumstances such as vigorous exercise as well as certain medications (eg, succinylcholine, statins) due to risk of rhabdomyolysis

Refs: 2252364; 7874115; 9731190; 12825073; 21634085

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHKA1 variants in ClinVar

12 Conditions Cataloged

Glycogen storage disease IXdTotal: 552

not providedTotal: 169

Inborn genetic diseasesTotal: 113

not specifiedTotal: 67

PHKA1-related disorderTotal: 30

Glycogen phosphorylase kinase deficiencyTotal: 7

Glycogen storage diseaseTotal: 2

Incidental DiscoveryTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002637.4. 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			28 clinvar	128 clinvar	7 clinvar	163
missense	2 clinvar		432 clinvar	32 clinvar		466
nonsense	13 clinvar	12 clinvar	18 clinvar			43
start loss						0
frameshift	10 clinvar	3 clinvar	3 clinvar			16
splice donor/acceptor (+/-2bp)	1 clinvar	16 clinvar	49 clinvar			66
Total	26	31	530	160	7	754

Highest pathogenic variant AF is 0.000014948974

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002637.4	RefSeq	NP_002628.2	32	MANE Select
ENST00000373542.9	Ensembl	ENSP00000362643.4	32	MANE Select
NM_001122670.2	RefSeq	NP_001116142.1	31	Standard
NM_001172436.2	RefSeq	NP_001165907.1	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucagon signaling pathway - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Insulin signaling pathway - Homo sapiens (human)
Glycogen Metabolism
Metabolism of carbohydrates

Biological Process

glycogen metabolic process
generation of precursor metabolites and energy
protein phosphorylation

Molecular Function

phosphorylase kinase activity
calmodulin binding

Cellular Component

cytosol
plasma membrane
phosphorylase kinase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373542
Coding exons: 32
Length: 135504
Individuals with no LoFs: 125714
Homozygous LoFs: 13
Heterozygous LoFs: 20
Defined: 125747
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.88	363	479	0.758	0.0000368	7976
Missense (PolyPhen)		94	151.89	0.61887		2513
Synonymous	-0.546	177	168	1.05	0.0000123	2386
Loss of Function	4.33	22	57.4	0.383	0.00000484	858

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.00012	rare
Latino/Admixed American	0.000037	0.000029	rare
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0.00036	0.00027	rare
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.00020	0.00014	rare
South Asian	0.00032	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin.;
Disease: DISEASE: Glycogen storage disease 9D (GSD9D) [MIM:300559]: A metabolic disorder characterized by slowly progressive, predominantly distal muscle weakness and atrophy. Clinical features include exercise intolerance with early fatigability, pain, cramps and occasionally myoglobinuria. {ECO:0000269|PubMed:12825073}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.190

Intolerance Scores

LoFtool: 0.0318
RVIS EVS: -0.8
RVIS percentile EVS: 12.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.184

Gene Damage Prediction

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