PHKA1

Summary

PHKA1 (phosphorylase kinase regulatory subunit alpha 1, HGNC:8925) is a protein-coding gene on chromosome Xq13.1, encoding Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform (P46020). Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.

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.

Source: NCBI Gene 5255 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease IXd (Definitive, ClinGen)
• Clinical variants (ClinVar): 940 total — 30 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• MANE Select transcript: NM_002637

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8925
Approved symbol	PHKA1
Name	phosphorylase kinase regulatory subunit alpha 1
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000067177
Ensembl biotype	protein_coding
OMIM	311870
Entrez	5255

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000339490, ENST00000373539, ENST00000373542, ENST00000373545, ENST00000541944, ENST00000898176, ENST00000898177, ENST00000929439, ENST00000929440, ENST00000958858, ENST00000958859, ENST00000958860, ENST00000958861, ENST00000958862

RefSeq mRNA: 4 — MANE Select: NM_002637 NM_001122670, NM_001172436, NM_001431068, NM_002637

CCDS: CCDS14421, CCDS48137, CCDS55453

Canonical transcript exons

ENST00000373542 — 32 exons

Exon	Start	End
ENSE00000379228	72684498	72684580
ENSE00000379229	72676070	72676150
ENSE00000379231	72666151	72666297
ENSE00000379234	72653435	72653530
ENSE00000379236	72650390	72650468
ENSE00000379237	72644362	72644496
ENSE00000379239	72635155	72635299
ENSE00000379255	72582398	72582598
ENSE00000672753	72584249	72584302
ENSE00000672759	72602158	72602273
ENSE00000672761	72603119	72603220
ENSE00000672763	72605271	72605400
ENSE00000672765	72605541	72605619
ENSE00000672769	72611028	72611184
ENSE00000672772	72618710	72618849
ENSE00000672777	72620725	72620901
ENSE00000672780	72623109	72623275
ENSE00000672782	72626971	72627049
ENSE00000672793	72636277	72636386
ENSE00000672798	72652544	72652651
ENSE00000672800	72656120	72656242
ENSE00000672801	72657588	72657641
ENSE00000672803	72667375	72667473
ENSE00000672807	72695708	72695876
ENSE00000859625	72593104	72593274
ENSE00000859626	72601991	72602029
ENSE00001266844	72619214	72619305
ENSE00001308105	72705198	72705245
ENSE00001659245	72609624	72609703
ENSE00001750427	72712779	72712937
ENSE00001861977	72578814	72581175
ENSE00001924839	72713803	72714306

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 95.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.3365 / max 52.4512, expressed in 1268 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199594	3.2209	1245
209733	0.1156	37

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	95.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.49	gold quality
biceps brachii	UBERON:0001507	95.30	gold quality
muscle of leg	UBERON:0001383	94.74	gold quality
vastus lateralis	UBERON:0001379	94.54	gold quality
muscle organ	UBERON:0001630	94.53	gold quality
quadriceps femoris	UBERON:0001377	94.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.69	gold quality
skeletal muscle tissue	UBERON:0001134	93.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.82	gold quality
deltoid	UBERON:0001476	92.30	gold quality
tibialis anterior	UBERON:0001385	90.94	silver quality
muscle tissue	UBERON:0002385	88.27	gold quality
triceps brachii	UBERON:0001509	87.78	gold quality
right adrenal gland cortex	UBERON:0035827	87.58	gold quality
left adrenal gland	UBERON:0001234	87.05	gold quality
right adrenal gland	UBERON:0001233	86.90	gold quality
gluteal muscle	UBERON:0002000	86.74	gold quality
left adrenal gland cortex	UBERON:0035825	86.69	gold quality
adrenal cortex	UBERON:0001235	85.52	gold quality
diaphragm	UBERON:0001103	85.26	gold quality
body of tongue	UBERON:0011876	85.13	gold quality
adrenal gland	UBERON:0002369	84.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.62	gold quality
medial globus pallidus	UBERON:0002477	81.30	gold quality
islet of Langerhans	UBERON:0000006	81.04	gold quality
ventricular zone	UBERON:0003053	81.00	gold quality
thoracic aorta	UBERON:0001515	80.47	gold quality
caudate nucleus	UBERON:0001873	80.46	gold quality
ascending aorta	UBERON:0001496	80.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-36552	yes	70.16
E-ANND-3	yes	5.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

157 targeting PHKA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-557	99.96	70.01	1640

Literature-anchored findings (GeneRIF, showing 4)

• alpha- and beta-subunits possess amino-terminal glucoamylase-like domains and suggests that they might possess a previously overlooked amylase activity (PMID:12876330)
• X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally (PMID:18401027)
• muscle PHKA deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle (PMID:22238410)
• A novel PHKA1 mutation associating myopathy and cognitive impairment: Expanding the spectrum of phosphorylase kinase b (PhK) deficiency. (PMID:33799212)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Phka1	ENSMUSG00000034055
rattus_norvegicus	Phka1	ENSRNOG00000003063

Paralogs (2): PHKA2 (ENSG00000044446), PHKB (ENSG00000102893)

Protein

Protein identifiers

Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform — P46020 (reviewed: P46020)

All UniProt accessions (3): P46020, A6NIT2, A6NMN0

UniProt curated annotations — full annotation on UniProt →

Function. Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin.

Subunit / interactions. Hexadecamer of 4 heterotetramers, each composed of alpha, beta, gamma, and delta subunits. Alpha (PHKA1 or PHKA2) and beta (PHKB) are regulatory subunits, gamma (PHKG1 or PHKG2) is the catalytic subunit, and delta is calmodulin.

Subcellular location. Cell membrane.

Tissue specificity. Muscle specific. Isoform 1 is predominant in vastus lateralis muscle. Isoform 2 predominates slightly in heart, and it predominates clearly in the other tissues tested.

Post-translational modifications. Although the final Cys may be farnesylated, the terminal tripeptide is probably not removed, and the C-terminus is not methylated.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. By phosphorylation of various serine residues. Allosteric regulation by calcium.

Pathway. Glycan biosynthesis; glycogen metabolism.

Similarity. Belongs to the phosphorylase b kinase regulatory chain family.

Isoforms (3)

UniProt ID	Names	Canonical?
P46020-1	1, AC	yes
P46020-2	2, C
P46020-3	3

RefSeq proteins (4): NP_001116142, NP_001165907, NP_001417997, NP_002628* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008734	PHK_A/B_su	Family
IPR008928	6-hairpin_glycosidase_sf	Homologous_superfamily
IPR011613	GH15-like	Domain
IPR012341	6hp_glycosidase-like_sf	Homologous_superfamily
IPR045583	KPBA/B_C	Domain

Pfam: PF00723, PF19292

Enzyme classification (BRENDA):

• EC 2.7.11.19 — phosphorylase kinase (BRENDA: 23 organisms, 150 substrates, 165 inhibitors, 89 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.018–0.95	16
PHOSPHORYLASE B	0.01–0.37	16
MGATP2-	0.07–0.1	9
S-PEPTIDE	0.21–0.28	2
SER-ASP-GLN-GLU-LYS-ARG-LYS-GLN-ILE-SER-VAL-ASP-	1.2–3.5	2
TETRADECAPEPTIDE	0.3085–0.47	2
GLYCOGEN PHOSPHORYLASE B	0.0093	1
GTP	0.6	1
MELITTIN	0.0098	1
SER-ASP-GLN-GLU-LYS-ARG-LYS-GLN-ILE-SER-VAL-ASP	2	1
UTP	1.4	1

UniProt features (124 total): helix 54, strand 28, turn 19, modified residue 12, region of interest 3, splice variant 3, chain 1, lipid moiety-binding region 1, sequence variant 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8XYA	ELECTRON MICROSCOPY	2.7
8JFK	ELECTRON MICROSCOPY	2.9
8JFL	ELECTRON MICROSCOPY	2.9
8XY7	ELECTRON MICROSCOPY	2.9
8XYB	ELECTRON MICROSCOPY	3.1
8Z5P	ELECTRON MICROSCOPY	3.41
8Z5R	ELECTRON MICROSCOPY	3.52
8Z5M	ELECTRON MICROSCOPY	3.66
8Z5T	ELECTRON MICROSCOPY	3.74
8Z5Q	ELECTRON MICROSCOPY	4.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46020-F1	81.84	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 981, 985, 1007, 1018, 1020, 1023, 1113, 1220, 629, 729, 735, 758, 972

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-70221	Glycogen breakdown (glycogenolysis)
R-HSA-1430728	Metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives
R-HSA-8982491	Glycogen metabolism

MSigDB gene sets: 211 (showing top): WWTAAGGC_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOBP_POSITIVE_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_GLYCOGEN_METABOLIC_PROCESS, BOYLAN_MULTIPLE_MYELOMA_D_CLUSTER_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS

GO Biological Process (4): glycogen metabolic process (GO:0005977), generation of precursor metabolites and energy (GO:0006091), positive regulation of glycogen catabolic process (GO:0045819), carbohydrate metabolic process (GO:0005975)

GO Molecular Function (3): phosphorylase kinase activity (GO:0004689), calmodulin binding (GO:0005516), protein binding (GO:0005515)

GO Cellular Component (5): cytosol (GO:0005829), plasma membrane (GO:0005886), phosphorylase kinase complex (GO:0005964), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glycogen metabolism	1
Metabolism	1
Metabolism of carbohydrates and carbohydrate derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
energy reserve metabolic process	1
glucan metabolic process	1
metabolic process	1
glycogen catabolic process	1
regulation of glycogen catabolic process	1
positive regulation of catabolic process	1
positive regulation of glycogen metabolic process	1
primary metabolic process	1
calcium/calmodulin-dependent protein kinase activity	1
protein binding	1
binding	1
membrane	1
cell periphery	1
serine/threonine protein kinase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHKA1	PHKG2	P11800	961
PHKA1	PHKG1	Q16816	928
PHKA1	RPS4X	P12631	806
PHKA1	RPS4Y1	P22090	778
PHKA1	PRKAG3	Q9UGI9	759
PHKA1	CETN3	O15182	638
PHKA1	TAF1	P21675	637
PHKA1	PYGM	P11217	607
PHKA1	CALM1	P02593	600
PHKA1	AGL	P35573	586
PHKA1	A0A590UK56	A0A590UK56	585
PHKA1	PYGL	P06737	574
PHKA1	SLC16A2	P36021	574
PHKA1	GBE1	Q04446	565
PHKA1	GYS1	P13807	560

IntAct

30 interactions, top by confidence:

A	B	Type	Score
PHKG2	PHKA2	psi-mi:“MI:0914”(association)	0.920
SOD1	CCS	psi-mi:“MI:0914”(association)	0.830
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
MPPED1	TXNDC9	psi-mi:“MI:0914”(association)	0.640
PHKG2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PHKG2	N4BP1	psi-mi:“MI:0914”(association)	0.350
CALM1	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM2	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PHKG2	PRPF40A	psi-mi:“MI:0914”(association)	0.350
SAP18	CASC3	psi-mi:“MI:0914”(association)	0.350
PHKA2	GYG2	psi-mi:“MI:0914”(association)	0.350
RDX	RNF113A	psi-mi:“MI:0914”(association)	0.350
GEMIN4	PHKA1	psi-mi:“MI:0914”(association)	0.350
COMTD1	TARS3	psi-mi:“MI:0914”(association)	0.350
PHKA2	STK25	psi-mi:“MI:0914”(association)	0.350
COMTD1	TNPO2	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MTX2	RP2	psi-mi:“MI:0914”(association)	0.350
PHKG2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SLC1A3	DDX11L8	psi-mi:“MI:0914”(association)	0.350
SLC67A1	LTN1	psi-mi:“MI:0914”(association)	0.350
SLC27A4	IPO5	psi-mi:“MI:0914”(association)	0.350
SLC2A9	EXOC5	psi-mi:“MI:0914”(association)	0.350
SPNS2	ESYT2	psi-mi:“MI:0914”(association)	0.350
PHKG2	NDUFA4	psi-mi:“MI:0914”(association)	0.350
PTPRT	PHKA1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (63): PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Proximity Label-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-MS), PHKA1 (Affinity Capture-RNA), TUBGCP4 (Two-hybrid)

ESM2 similar proteins: A0A6A6H2E0, F1LXS7, O24301, O49845, P04712, P0C9D3, P0C9D4, P10691, P12798, P13708, P18688, P18826, P30298, P31850, P31922, P31923, P31924, P46018, P46019, P46020, P49034, P49036, P49037, P76484, Q00917, Q01390, Q09400, Q10LP5, Q12351, Q41608, Q42652, Q43009, Q4H4F7, Q53E76, Q64649, Q65159, Q6K973, Q6L8K1, Q6L8L3, Q79V62

Diamond homologs: P12798, P18688, P18826, P34335, P46018, P46019, P46020, Q64649, Q7TSH2, Q8BWJ3, Q93100, Q9VLS1, Q9W391, Q9W6R1

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
PHKA1	“down-regulates activity”	PHKG1	binding
PHKA1	“down-regulates activity”	PHKG2	binding
PKA	“down-regulates activity”	PHKA1	phosphorylation
PRKACA	“up-regulates activity”	PHKA1	phosphorylation
PRKACB	“down-regulates activity”	PHKA1	phosphorylation
PRKACG	“down-regulates activity”	PHKA1	phosphorylation
PHKA1	“up-regulates activity”	PHKA1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

940 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	22
Uncertain significance	372
Likely benign	227
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033522	NM_002637.4(PHKA1):c.2603_2604del (p.Ser868fs)	Pathogenic
1356420	NM_002637.4(PHKA1):c.1759C>T (p.Arg587Ter)	Pathogenic
1413850	NM_002637.4(PHKA1):c.812_813dup (p.Asp272fs)	Pathogenic
1686058	NM_002637.4(PHKA1):c.635T>G (p.Leu212Ter)	Pathogenic
1711712	NM_002637.4(PHKA1):c.2050G>T (p.Gly684Ter)	Pathogenic
1935503	NM_002637.4(PHKA1):c.2460dup (p.Arg821fs)	Pathogenic
2865051	NM_002637.4(PHKA1):c.2683C>T (p.Gln895Ter)	Pathogenic
2869668	NM_002637.4(PHKA1):c.2587C>T (p.Arg863Ter)	Pathogenic
2877713	NM_002637.4(PHKA1):c.1531dup (p.Tyr511fs)	Pathogenic
2879436	NM_002637.4(PHKA1):c.2755C>T (p.Arg919Ter)	Pathogenic
3056727	NM_002637.4(PHKA1):c.2911C>T (p.Arg971Ter)	Pathogenic
3653269	NM_002637.4(PHKA1):c.713del (p.Cys238fs)	Pathogenic
3683387	NM_002637.4(PHKA1):c.2716C>T (p.Arg906Ter)	Pathogenic
3700118	NM_002637.4(PHKA1):c.1489C>T (p.Arg497Ter)	Pathogenic
3721392	NM_002637.4(PHKA1):c.2847_2848del (p.Pro951fs)	Pathogenic
3726560	NM_002637.4(PHKA1):c.1123_1124del (p.Val375fs)	Pathogenic
4627392	NM_002637.4(PHKA1):c.2329C>T (p.Gln777Ter)	Pathogenic
4749234	NM_002637.4(PHKA1):c.2335C>T (p.Gln779Ter)	Pathogenic
4823830	NM_002637.4(PHKA1):c.2695_2696delinsCACACAGTCATATGCATAC (p.Val899fs)	Pathogenic
4849096	NM_002637.4(PHKA1):c.1571_1572dup (p.Ile525fs)	Pathogenic
578746	NM_002637.4(PHKA1):c.892C>T (p.Arg298Ter)	Pathogenic
584437	Single allele	Pathogenic
625792	GRCh37/hg19 Xq13.2(chrX:71801020-71804146)	Pathogenic
832096	NC_000023.11:g.(?72644342)(72676170_?)del	Pathogenic
987457	NM_002637.4(PHKA1):c.1039C>T (p.Gln347Ter)	Pathogenic
9923	NM_002637.4(PHKA1):c.3334G>T (p.Glu1112Ter)	Pathogenic
9924	NM_002637.4(PHKA1):c.3498+1G>C	Pathogenic
9925	NM_002637.4(PHKA1):c.896A>T (p.Asp299Val)	Pathogenic
9926	NM_002637.4(PHKA1):c.695del (p.Ala232fs)	Pathogenic
9927	NM_002637.4(PHKA1):c.667G>A (p.Gly223Arg)	Pathogenic

SpliceAI

4065 predictions. Top by Δscore:

Variant	Effect	Δscore
X:72581187:T:TC	acceptor_gain	1.0000
X:72581193:G:C	acceptor_gain	1.0000
X:72581193:G:GC	acceptor_gain	1.0000
X:72582393:CCTA:C	donor_loss	1.0000
X:72582394:CTAC:C	donor_loss	1.0000
X:72582395:TACC:T	donor_loss	1.0000
X:72582396:A:AC	donor_gain	1.0000
X:72582397:C:CA	donor_loss	1.0000
X:72582397:C:CC	donor_gain	1.0000
X:72582594:GTCAT:G	acceptor_gain	1.0000
X:72582595:TCAT:T	acceptor_gain	1.0000
X:72582596:CAT:C	acceptor_gain	1.0000
X:72582596:CATC:C	acceptor_gain	1.0000
X:72582597:AT:A	acceptor_gain	1.0000
X:72582599:C:CC	acceptor_gain	1.0000
X:72582601:G:C	acceptor_gain	1.0000
X:72584243:TCTTA:T	donor_loss	1.0000
X:72584244:CTTA:C	donor_loss	1.0000
X:72584245:TTA:T	donor_loss	1.0000
X:72584246:TAC:T	donor_loss	1.0000
X:72584247:A:T	donor_loss	1.0000
X:72584248:CCT:C	donor_gain	1.0000
X:72584248:CCTCT:C	donor_gain	1.0000
X:72584298:TGACA:T	acceptor_gain	1.0000
X:72584299:GACA:G	acceptor_gain	1.0000
X:72584299:GACAC:G	acceptor_loss	1.0000
X:72584300:ACACT:A	acceptor_loss	1.0000
X:72584301:CA:C	acceptor_gain	1.0000
X:72584302:AC:A	acceptor_loss	1.0000
X:72584303:C:A	acceptor_loss	1.0000

AlphaMissense

7995 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:72581081:C:T	G1198D	1.000
X:72582519:A:G	L1126P	1.000
X:72593173:T:A	R1058S	1.000
X:72593173:T:G	R1058S	1.000
X:72593174:C:G	R1058T	1.000
X:72593185:C:A	W1054C	1.000
X:72593185:C:G	W1054C	1.000
X:72593187:A:G	W1054R	1.000
X:72593187:A:T	W1054R	1.000
X:72656179:A:G	W328R	1.000
X:72656179:A:T	W328R	1.000
X:72676138:A:G	W184R	1.000
X:72676138:A:T	W184R	1.000
X:72581066:A:G	L1203P	0.999
X:72581070:A:C	Y1202D	0.999
X:72581081:C:A	G1198V	0.999
X:72581082:C:G	G1198R	0.999
X:72582423:G:T	A1158D	0.999
X:72582510:T:A	E1129V	0.999
X:72582525:C:G	R1124P	0.999
X:72582526:G:T	R1124S	0.999
X:72582552:A:G	L1115P	0.999
X:72582576:A:G	F1107S	0.999
X:72584271:A:G	L1092P	0.999
X:72584292:A:G	L1085P	0.999
X:72593162:C:T	G1062E	0.999
X:72593163:C:A	G1062W	0.999
X:72593163:C:G	G1062R	0.999
X:72593163:C:T	G1062R	0.999
X:72593174:C:A	R1058I	0.999

dbSNP variants (sampled 300 via entrez): RS1000387651 (X:72711153 G>A), RS1000410240 (X:72646048 T>C), RS1000559511 (X:72692511 G>A,C,T), RS1000661551 (X:72703118 C>A), RS1000664084 (X:72689982 T>C), RS1000715772 (X:72617216 G>T), RS1000775645 (X:72703585 G>A), RS1000778428 (X:72628121 G>A), RS1000841046 (X:72626500 A>G), RS1000849126 (X:72701629 G>A), RS1000851269 (X:72655703 G>A), RS1000902150 (X:72655872 G>A), RS1000908206 (X:72693363 A>C,G), RS1000970027 (X:72668347 G>A,C), RS1001015005 (X:72597558 T>C)

Disease associations

OMIM: gene MIM:311870 | disease phenotypes: MIM:300559, MIM:311250, MIM:232200, MIM:300882

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease IXd	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glycogen storage disease IXd	Definitive	XL

Mondo (7): glycogen storage disease IXd (MONDO:0010362), glycogen storage disease IX (MONDO:0700291), peripheral neuropathy (MONDO:0005244), intellectual disability (MONDO:0001071), ornithine carbamoyltransferase deficiency (MONDO:0010703), disorder of glycogen metabolism (MONDO:0002412), Cornelia de Lange syndrome 5 (MONDO:0010471)

Orphanet (6): Glycogen storage disease due to muscle phosphorylase kinase deficiency (Orphanet:715), Glycogen storage disease due to phosphorylase kinase deficiency (Orphanet:370), Ornithine transcarbamylase deficiency (Orphanet:664), Glycogen storage disease (Orphanet:79201), Cornelia de Lange syndrome (Orphanet:199), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0001265	Hyporeflexia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001419	X-linked recessive inheritance
HP:0001943	Hypoglycemia
HP:0002460	Distal muscle weakness
HP:0002913	Myoglobinuria
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003323	Progressive muscle weakness
HP:0003326	Myalgia
HP:0003391	Gowers sign
HP:0003394	Muscle spasm
HP:0003458	EMG: myopathic abnormalities
HP:0003546	Exercise intolerance
HP:0003551	Difficulty climbing stairs
HP:0003596	Middle age onset
HP:0003693	Distal amyotrophy
HP:0003713	Muscle fiber necrosis
HP:0003731	Quadriceps muscle weakness
HP:0003738	Exercise-induced myalgia
HP:0003749	Pelvic girdle muscle weakness
HP:0007340	Lower limb muscle weakness
HP:0008305	Exercise-induced myoglobinuria
HP:0008967	Exercise-induced muscle stiffness
HP:0009051	Increased muscle glycogen content
HP:0012378	Fatigue
HP:0030231	Glycogen accumulation in muscle fiber lysosomes
HP:0100595	Camptocormia
HP:6000198	Reduced muscle phosphorylase kinase activity

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020163	Ornithine Carbamoyltransferase Deficiency Disease	C10.228.140.163.100.937.750; C16.320.322.828; C16.320.565.100.940.750; C16.320.565.189.937.750; C18.452.132.100.937.500; C18.452.648.100.940.500; C18.452.648.189.937.500
C580130	Glycogen Storage Disease Type Ix (supp.)
C564485	Glycogen Storage Disease, Type IXD (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2111324 (PROTEIN COMPLEX GROUP)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

5 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	STAUROSPORINE
8.77	IC50	1.7	nM	K-252A
5.77	IC50	1688	nM	CHEMBL538718
5.42	IC50	3800	nM	CHEMBL538718

PubChem BioAssay actives

3 with measured affinity, of 45 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	159258: Inhibition of phosphorylase kinase.	ic50	0.0005	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	1405290: Inhibition of phosphorylase kinase (unknown origin)	ic50	0.0017	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment	2
Particulate Matter	increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases abundance, increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	affects expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Amiodarone	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Rotenone	decreases expression	1
Tretinoin	decreases expression	1
Vanadates	decreases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020729	Binding	Inhibition of human PHK at 10 umol/L	Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3DT	Abcam HEK293T PHKA1 KO	Transformed cell line	Female
CVCL_D7WW	Ubigene A-549 PHKA1 KO	Cancer cell line	Male
CVCL_D8S8	Ubigene HCT 116 PHKA1 KO	Cancer cell line	Male
CVCL_D9MQ	Ubigene HEK293 PHKA1 KO	Transformed cell line	Female
CVCL_E0K4	Ubigene HeLa PHKA1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.