PHKA2

Summary

PHKA2 (phosphorylase kinase regulatory subunit alpha 2, HGNC:8926) is a protein-coding gene on chromosome Xp22.13, encoding Phosphorylase b kinase regulatory subunit alpha, liver isoform (P46019). 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 hepatic 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 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.

Source: NCBI Gene 5256 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease IXa1 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 923 total — 62 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes
• MANE Select transcript: NM_000292

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8926
Approved symbol	PHKA2
Name	phosphorylase kinase regulatory subunit alpha 2
Location	Xp22.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000044446
Ensembl biotype	protein_coding
OMIM	300798
Entrez	5256

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 18 protein_coding, 7 protein_coding_CDS_not_defined

ENST00000379942, ENST00000464455, ENST00000469485, ENST00000469645, ENST00000473597, ENST00000473739, ENST00000481718, ENST00000486231, ENST00000897867, ENST00000897868, ENST00000897869, ENST00000897870, ENST00000897871, ENST00000897872, ENST00000897873, ENST00000934920, ENST00000934921, ENST00000934922, ENST00000934923, ENST00000954727, ENST00000954728, ENST00000954729, ENST00000954730, ENST00000954731, ENST00000954732

RefSeq mRNA: 1 — MANE Select: NM_000292 NM_000292

CCDS: CCDS14190

Canonical transcript exons

ENST00000379942 — 33 exons

Exon	Start	End
ENSE00000551761	18910872	18910960
ENSE00000551767	18920032	18920201
ENSE00000551768	18918681	18918854
ENSE00000551774	18938627	18938749
ENSE00000666379	18907900	18908056
ENSE00000666380	18908801	18908934
ENSE00000666450	18939995	18940048
ENSE00000843133	18906736	18906814
ENSE00000843141	18943710	18943808
ENSE00000843142	18945078	18945158
ENSE00001108522	18936055	18936150
ENSE00001108527	18948744	18948826
ENSE00001108536	18929228	18929306
ENSE00001108539	18952494	18952541
ENSE00001108545	18941529	18941675
ENSE00001108550	18924381	18924525
ENSE00001108552	18924056	18924134
ENSE00001108554	18951104	18951272
ENSE00001200858	18931641	18931748
ENSE00001249835	18926453	18926587
ENSE00001483126	18892298	18893655
ENSE00001483162	18983855	18984114
ENSE00001639162	18907018	18907097
ENSE00001804731	18954254	18954412
ENSE00003476207	18900670	18900699
ENSE00003476331	18897163	18897333
ENSE00003575024	18905758	18905859
ENSE00003598223	18895138	18895191
ENSE00003615330	18925668	18925777
ENSE00003640169	18899173	18899226
ENSE00003674449	18901485	18901603
ENSE00003691763	18906495	18906624
ENSE00003692242	18894204	18894404

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 97.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.9806 / max 119.1715, expressed in 1557 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198595	1.7639	925
198597	1.2216	661
209619	0.4664	261
198596	0.4271	204
198598	0.3282	122
198599	0.3093	167
198593	0.2497	83
198594	0.2143	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.10	gold quality
right uterine tube	UBERON:0001302	94.95	gold quality
apex of heart	UBERON:0002098	94.74	gold quality
left ovary	UBERON:0002119	94.16	gold quality
body of pancreas	UBERON:0001150	94.12	gold quality
pituitary gland	UBERON:0000007	93.61	gold quality
adenohypophysis	UBERON:0002196	93.50	gold quality
right ovary	UBERON:0002118	93.15	gold quality
liver	UBERON:0002107	92.47	gold quality
left lobe of thyroid gland	UBERON:0001120	92.13	gold quality
right lobe of thyroid gland	UBERON:0001119	92.12	gold quality
body of uterus	UBERON:0009853	92.08	gold quality
granulocyte	CL:0000094	91.99	gold quality
heart left ventricle	UBERON:0002084	91.67	gold quality
left adrenal gland cortex	UBERON:0035825	91.42	gold quality
cardiac ventricle	UBERON:0002082	91.32	gold quality
right adrenal gland	UBERON:0001233	91.29	gold quality
thyroid gland	UBERON:0002046	91.25	gold quality
left testis	UBERON:0004533	91.15	gold quality
right testis	UBERON:0004534	91.14	gold quality
right atrium auricular region	UBERON:0006631	91.10	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.99	gold quality
right adrenal gland cortex	UBERON:0035827	90.98	gold quality
left adrenal gland	UBERON:0001234	90.97	gold quality
ovary	UBERON:0000992	90.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.73	gold quality
adrenal cortex	UBERON:0001235	90.60	gold quality
pancreatic ductal cell	CL:0002079	90.50	silver quality
cardiac atrium	UBERON:0002081	90.39	gold quality
cerebellar hemisphere	UBERON:0002245	90.38	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting PHKA2, 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-5193	100.00	67.26	1744
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-7703	97.64	67.00	965
HSA-MIR-192-3P	97.52	67.66	1001
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-4693-3P	95.23	65.92	735
HSA-MIR-4793-3P	94.87	65.85	896
HSA-MIR-4749-5P	92.16	62.26	179

Literature-anchored findings (GeneRIF, showing 13)

• Gene analysis was confirmed to represent a useful procedure for diagnosing x-linked liver glycogenosis, for which liver biopsy had previously been required to detect hepatic phosphorylase kinase deficiency (PMID:12862311)
• alpha- and beta-subunits possess amino-terminal glucoamylase-like domains and suggests that they might possess a previously overlooked amylase activity (PMID:12876330)
• Alu-mediated, large deletion-spanning introns 19-26 in PHKA2 is associated with X-linked liver glycogenosis (PMID:17581768)
• Results show that phosphorylase kinase (PhK) alpha subunit missense mutations or small in-frame deletions/insertions may have a direct impact on the PhK alpha functions. (PMID:18950708)
• two novel mutations found in two GSD type IX patients with different residual enzyme activities (PMID:21131218)
• The present case also represents the first known reported case of liver PhK deficiency with an PHKA2 mutation and liver cirrhosis. (PMID:21857251)
• We found that the missense mutation p.Pro1205Leu in the PHKA2 gene is a common cause of hepatic phosphorylase-kinase deficiency in Dutch patients, suggesting a founder-effect (PMID:21911307)
• In this study we summarized the PHKA2 mutation spectrum in Korean glycogen storage disease type IX patients and found that the most common mutation type was gross deletion. (PMID:27103379)
• Clinical data and analyzed the PHKA2 gene of 17 Chinese male patients suspected of having Glycogen storage disease (GSD) type IXa; study detected 14 mutations in 17 patients, including 8 novel mutations; exons 2 and 4 were hot spots. (PMID:28627441)
• Study identified a novel mutation in PHKA2 (c.2972C > G, p.G991A) in patients with relatively rare phenotype of GSD IXa, including hypoglycaemia and delayed motor development. (PMID:30925902)
• A novel frameshift PHKA2 mutation in a family with glycogen storage disease type IXa: A first report in Vietnam and review of literature. (PMID:32387637)
• Benign or not benign? Deep phenotyping of liver Glycogen Storage Disease IX. (PMID:33317799)
• PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only. (PMID:34117828)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	phka2	ENSDARG00000030687
mus_musculus	Phka2	ENSMUSG00000031295
rattus_norvegicus	AABR07037995.1	ENSRNOG00000003949
drosophila_melanogaster	CG7766	FBGN0030087
caenorhabditis_elegans		WBGENE00015754

Paralogs (2): PHKA1 (ENSG00000067177), PHKB (ENSG00000102893)

Protein

Protein identifiers

Phosphorylase b kinase regulatory subunit alpha, liver isoform — P46019 (reviewed: P46019)

All UniProt accessions (1): P46019

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. Predominantly expressed in liver and other non-muscle tissues.

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 9A (GSD9A) [MIM:306000] A metabolic disorder resulting in a mild liver glycogenosis with clinical symptoms that include hepatomegaly, growth retardation, muscle weakness, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis. Two subtypes are known: type 1 or classic type with no phosphorylase kinase activity in liver or erythrocytes, and type 2 or variant type with no phosphorylase kinase activity in liver, but normal activity in erythrocytes. Unlike other glycogenosis diseases, glycogen storage disease type 9A is generally a benign condition. Patients improve with age and are often asymptomatic as adults. Accurate diagnosis is therefore also of prognostic interest. The disease is caused by variants affecting the gene represented in this entry.

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

Pathway. Glycan biosynthesis; glycogen metabolism.

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

RefSeq proteins (1): NP_000283* (*=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 (43 total): sequence variant 27, modified residue 6, region of interest 4, sequence conflict 2, compositionally biased region 2, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46019-F1	81.36	0.50

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 (7): 983, 1015, 1044, 1232, 695, 729, 735

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: 271 (showing top): MOOTHA_GLYCOGEN_METABOLISM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MODULE_308, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, TSENG_IRS1_TARGETS_DN, GOBP_CARBOHYDRATE_CATABOLIC_PROCESS, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, CTAWWWATA_RSRFC4_Q2, SASSON_RESPONSE_TO_GONADOTROPHINS_UP

GO Biological Process (4): carbohydrate metabolic process (GO:0005975), glycogen metabolic process (GO:0005977), generation of precursor metabolites and energy (GO:0006091), protein modification process (GO:0036211)

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
primary metabolic process	1
energy reserve metabolic process	1
glucan metabolic process	1
metabolic process	1
protein metabolic process	1
macromolecule modification	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

912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHKA2	PHKG2	P11800	958
PHKA2	PHKG1	Q16816	919
PHKA2	CALM1	P02593	661
PHKA2	A0A590UK56	A0A590UK56	622
PHKA2	GPI	P06744	610
PHKA2	PYGL	P06737	590
PHKA2	PFKM	P08237	576
PHKA2	AGL	P35573	547
PHKA2	TPI1	P00938	541
PHKA2	GBE1	Q04446	518
PHKA2	SLC37A4	O43826	513
PHKA2	RPE	Q96AT9	507
PHKA2	ACSS2	Q9NR19	500
PHKA2	GYS2	P54840	497
PHKA2	PYGM	P11217	481

IntAct

58 interactions, top by confidence:

A	B	Type	Score
PHKG2	PHKA2	psi-mi:“MI:0915”(physical association)	0.920
PHKG2	PHKA2	psi-mi:“MI:0914”(association)	0.920
MPPED1	TXNDC9	psi-mi:“MI:0914”(association)	0.640
PHKG2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
MPPED1	CLUH	psi-mi:“MI:0914”(association)	0.640
PHKA2	PHKB	psi-mi:“MI:0915”(physical association)	0.560
UROD	PHKA2	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	PHKA2	psi-mi:“MI:0915”(physical association)	0.560
TCEANC2	HTATSF1	psi-mi:“MI:0914”(association)	0.530
PHKA2	STT3B	psi-mi:“MI:0915”(physical association)	0.400
Ndc80	RRBP1	psi-mi:“MI:0915”(physical association)	0.400
ARL5A	PHKA2	psi-mi:“MI:0915”(physical association)	0.400
PHKA2	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
Oxnad1	KPNA6	psi-mi:“MI:0914”(association)	0.350
Rmdn3	DERL1	psi-mi:“MI:0914”(association)	0.350
Ppp1r3b		psi-mi:“MI:0914”(association)	0.350
Mtx2	NRDC	psi-mi:“MI:0914”(association)	0.350
PHKG2	PEX10	psi-mi:“MI:0914”(association)	0.350
BAG6	CNOT1	psi-mi:“MI:0914”(association)	0.350
GOLT1B		psi-mi:“MI:0914”(association)	0.350
FOXK1	PHKG2	psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
HERC2	EIF3F	psi-mi:“MI:0914”(association)	0.350
TCEANC2	ANKHD1	psi-mi:“MI:0914”(association)	0.350
DOK4	SUPT5H	psi-mi:“MI:0914”(association)	0.350
PHKG2	N4BP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A023YYV9, A0A0H3NK84, A0A482PDI9, A0A656IJ15, A7ZP88, A9MJD1, A9N5C6, B7UI21, B7UNX3, D0ZIB5, O24301, P03589, P04712, P0A2N2, P0A2N3, P0DUJ7, P0DUJ8, P0DUW5, P27474, P30298, P31922, P31923, P37627, P37629, P39374, P46019, P76612, Q05608, Q09400, Q47013, Q57M66, Q5ZSQ2, Q5ZU30, Q5ZXN5, Q5ZZ30, Q67704, Q6R7I0, Q877R9, Q8VSJ7, Q8X837

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

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PHKA2	“down-regulates activity”	PHKG1	binding
PHKA2	“down-regulates activity”	PHKG2	binding
PKA	“down-regulates activity”	PHKA2	phosphorylation
PRKACA	“down-regulates activity”	PHKA2	phosphorylation
PRKACB	“down-regulates activity”	PHKA2	phosphorylation
PRKACG	“down-regulates activity”	PHKA2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cytokinesis	5	39.8×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	46
Uncertain significance	254
Likely benign	187
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1006299	NM_000292.3(PHKA2):c.2470C>T (p.Arg824Cys)	Pathogenic
1026764	NM_000292.3(PHKA2):c.893G>C (p.Arg298Pro)	Pathogenic
1028673	NM_000292.3(PHKA2):c.3529C>T (p.Gln1177Ter)	Pathogenic
10527	NM_000292.3(PHKA2):c.3025C>T (p.Gln1009Ter)	Pathogenic
10528	NM_000292.3(PHKA2):c.2296C>T (p.Gln766Ter)	Pathogenic
10529	NM_000292.3(PHKA2):c.717+1G>T	Pathogenic
10530	NM_000292.3(PHKA2):c.3146C>A (p.Ser1049Ter)	Pathogenic
10532	NM_000292.3(PHKA2):c.421_423del (p.Phe141del)	Pathogenic
10534	NM_000292.3(PHKA2):c.896A>G (p.Asp299Gly)	Pathogenic
10536	NM_000292.3(PHKA2):c.395A>C (p.His132Pro)	Pathogenic
10539	NM_000292.3(PHKA2):c.750_752del (p.Thr251del)	Pathogenic
10540	NM_000292.3(PHKA2):c.3327_3332dup (p.Arg1111_Glu1112insThrArg)	Pathogenic
1071224	NM_000292.3(PHKA2):c.3325del (p.Thr1109fs)	Pathogenic
1072784	NM_000292.3(PHKA2):c.2378_2379del (p.Thr793fs)	Pathogenic
1172621	NM_000292.3(PHKA2):c.3295_3296dup (p.Ile1100fs)	Pathogenic
1456672	NM_000292.3(PHKA2):c.2614G>T (p.Glu872Ter)	Pathogenic
1459330	NM_000292.3(PHKA2):c.2509_2510insATGTATAAATATGTAACTAACCTGCACAATGTGCACATGTACCCTAAAACTTATATTATAATAAAAAAAAAAAAAAAAAAATAACAATAAAATGAGATAAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAGTGGAGGTCC (p.Leu837delinsHisValTer)	Pathogenic
1686059	NM_000292.3(PHKA2):c.1324+1G>A	Pathogenic
1686060	NM_000292.3(PHKA2):c.1210C>T (p.Gln404Ter)	Pathogenic
1703196	NM_000292.3(PHKA2):c.892C>T (p.Arg298Ter)	Pathogenic
1809725	NM_000292.3(PHKA2):c.1387C>T (p.Gln463Ter)	Pathogenic
1810400	NM_000292.3(PHKA2):c.1969C>T (p.Gln657Ter)	Pathogenic
208493	NM_000292.3(PHKA2):c.883C>T (p.Arg295Cys)	Pathogenic
2101957	NM_000292.3(PHKA2):c.1420C>T (p.Gln474Ter)	Pathogenic
2138484	NM_000292.3(PHKA2):c.1174C>T (p.Arg392Ter)	Pathogenic
2422823	NC_000023.10:g.(?18925998)(18929098_?)del	Pathogenic
2571357	NM_000292.3(PHKA2):c.285+1del	Pathogenic
2696072	NM_000292.3(PHKA2):c.3329_3336+6del	Pathogenic
2700165	NM_000292.3(PHKA2):c.2783_2793del (p.Leu928fs)	Pathogenic
2767520	NM_000292.3(PHKA2):c.1502del (p.His501fs)	Pathogenic

SpliceAI

5189 predictions. Top by Δscore:

Variant	Effect	Δscore
X:18894189:C:CA	donor_gain	1.0000
X:18894198:CCCCA:C	donor_loss	1.0000
X:18894199:CCCAC:C	donor_loss	1.0000
X:18894200:CCACC:C	donor_loss	1.0000
X:18894201:CACC:C	donor_loss	1.0000
X:18894203:C:CT	donor_loss	1.0000
X:18894208:T:TA	donor_gain	1.0000
X:18894225:A:AC	donor_gain	1.0000
X:18894226:C:CC	donor_gain	1.0000
X:18894364:G:T	acceptor_gain	1.0000
X:18894400:GTCAT:G	acceptor_gain	1.0000
X:18894401:TCAT:T	acceptor_gain	1.0000
X:18894402:CAT:C	acceptor_gain	1.0000
X:18894402:CATC:C	acceptor_gain	1.0000
X:18894403:AT:A	acceptor_gain	1.0000
X:18894403:ATC:A	acceptor_loss	1.0000
X:18894404:TC:T	acceptor_loss	1.0000
X:18894405:C:CC	acceptor_gain	1.0000
X:18894405:CTA:C	acceptor_loss	1.0000
X:18894406:T:A	acceptor_loss	1.0000
X:18894409:C:CT	acceptor_gain	1.0000
X:18894410:A:T	acceptor_gain	1.0000
X:18894652:T:TA	donor_gain	1.0000
X:18906492:CAC:C	donor_loss	1.0000
X:18906493:ACC:A	donor_loss	1.0000
X:18906494:C:T	donor_loss	1.0000
X:18906622:CTC:C	acceptor_gain	1.0000
X:18906626:T:G	acceptor_loss	1.0000
X:18906631:C:CT	acceptor_gain	1.0000
X:18906632:A:T	acceptor_gain	1.0000

AlphaMissense

8123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:18897233:C:G	R1071T	1.000
X:18938686:A:G	W328R	1.000
X:18938686:A:T	W328R	1.000
X:18945144:C:A	W184C	1.000
X:18945144:C:G	W184C	1.000
X:18945146:A:G	W184R	1.000
X:18945146:A:T	W184R	1.000
X:18894325:A:G	L1139P	0.999
X:18894331:C:G	R1137P	0.999
X:18895181:A:G	L1098P	0.999
X:18897232:T:A	R1071S	0.999
X:18897232:T:G	R1071S	0.999
X:18897246:A:G	W1067R	0.999
X:18897246:A:T	W1067R	0.999
X:18905805:A:G	L954P	0.999
X:18906518:A:G	L928P	0.999
X:18907946:C:G	R824P	0.999
X:18907947:G:T	R824S	0.999
X:18907959:A:G	W820R	0.999
X:18907959:A:T	W820R	0.999
X:18931682:A:G	W402R	0.999
X:18931682:A:T	W402R	0.999
X:18938715:A:G	L318P	0.999
X:18940020:C:G	R298P	0.999
X:18940025:G:C	F296L	0.999
X:18940025:G:T	F296L	0.999
X:18940027:A:G	F296L	0.999
X:18940038:C:T	G292E	0.999
X:18941656:A:G	L246P	0.999
X:18943796:C:G	A211P	0.999

dbSNP variants (sampled 300 via entrez): RS1000013421 (X:18899438 A>G), RS1000066428 (X:18966346 C>T), RS1000068976 (X:18892305 TTG>T), RS1000069407 (X:18892835 C>T), RS1000100457 (X:18899764 G>A), RS1000163818 (X:18927033 T>C), RS1000211699 (X:18947958 C>A), RS1000258101 (X:18958295 C>T), RS1000297236 (X:18893420 G>A), RS1000325288 (X:18975148 T>C), RS1000346911 (X:18948248 A>G), RS1000400731 (X:18906477 G>C), RS1000519283 (X:18929950 C>A), RS1000556226 (X:18929344 TTAAC>T), RS1000557044 (X:18929725 A>C)

Disease associations

OMIM: gene MIM:300798 | disease phenotypes: MIM:306000, MIM:232200, MIM:300600, MIM:300559, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease IXa1	Definitive	X-linked
glycogen storage disease due to liver phosphorylase kinase deficiency	Supportive	Autosomal recessive

Mondo (9): glycogen storage disease IXa1 (MONDO:0010598), glycogen storage disease IX (MONDO:0700291), disorder of glycogen metabolism (MONDO:0002412), glycogen storage disease IXa2 (MONDO:0100439), Aland island eye disease (MONDO:0010371), glycogen storage disease IXd (MONDO:0010362), intellectual disability (MONDO:0001071), genetic developmental and epileptic encephalopathy (MONDO:0100062), glycogen storage disease due to liver phosphorylase kinase deficiency (MONDO:0020693)

Orphanet (6): Glycogen storage disease due to liver phosphorylase kinase deficiency (Orphanet:264580), Glycogen storage disease due to phosphorylase kinase deficiency (Orphanet:370), Glycogen storage disease (Orphanet:79201), Åland Islands eye disease (Orphanet:178333), Glycogen storage disease due to muscle phosphorylase kinase deficiency (Orphanet:715), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000147	Polycystic ovaries
HP:0000750	Delayed speech and language development
HP:0000823	Delayed puberty
HP:0000858	Irregular menstruation
HP:0000876	Oligomenorrhea
HP:0000939	Osteoporosis
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001638	Cardiomyopathy
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0001943	Hypoglycemia
HP:0001946	Ketosis
HP:0001947	Renal tubular acidosis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002040	Esophageal varix
HP:0002149	Hyperuricemia
HP:0002155	Hypertriglyceridemia
HP:0002194	Delayed gross motor development

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
D006015	Glycogen Storage Disease Type VIII	C16.320.322.217; C16.320.565.202.449.620; C18.452.648.202.449.620
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C562664	Aland Island Eye Disease (supp.)
C580130	Glycogen Storage Disease Type Ix (supp.)
C564485	Glycogen Storage Disease, Type IXD (supp.)
C564421	Liver Glycogenosis, X-Linked, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111324 (PROTEIN COMPLEX GROUP), CHEMBL2906 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 9 total, top 7 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
6.00	IC50	1000	nM	TP-030n
5.96	Kd	1108	nM	CHEMBL5653589
5.96	ED50	1108	nM	CHEMBL5653589
5.77	IC50	1688	nM	CHEMBL538718
5.42	IC50	3800	nM	CHEMBL538718

PubChem BioAssay actives

4 with measured affinity, of 47 total; 3 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148997: Binding affinity to human PHKA2 incubated for 45 mins by Kinobead based pull down assay	kd	1.1080	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
beauvericin	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	affects methylation	1
coumarin	increases phosphorylation	1
ciglitazone	affects binding, increases expression	1
M-VAC protocol	decreases response to substance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
enniatins	affects cotreatment, decreases expression	1
abrine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Niclosamide	decreases expression	1
Phenobarbital	affects expression	1
Phthalic Acids	decreases methylation	1
Quercetin	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

48 unique, capped per target: 48 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, 1 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3V0	KRIBBi003-A	Induced pluripotent stem cell	Male
CVCL_D7WX	Ubigene A-549 PHKA2 KO	Cancer cell line	Male
CVCL_D8S9	Ubigene HCT 116 PHKA2 KO	Cancer cell line	Male
CVCL_D9MR	Ubigene HEK293 PHKA2 KO	Transformed cell line	Female
CVCL_E0K5	Ubigene HeLa PHKA2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02782741	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease
NCT04808505	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, PK, PD and Immunogenicity of Cipaglucosidase Alfa/Miglustat in IOPD Subjects Aged 0 to <18
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00765414	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme for a Single Patient With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored ERT Studies.
NCT02032524	PHASE2	COMPLETED	Avalglucosidase Alfa Extension Study
NCT03019406	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT04454216	Not specified	RECRUITING	GSD VI and GSD IX Natural History
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT05095727	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)
NCT00001342	Not specified	COMPLETED	Study of Glycogen Storage Disease and Associated Disorders
NCT00566878	Not specified	COMPLETED	Pompe Lactation Sub-Registry
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02057731	Not specified	COMPLETED	Study of Glycogen Storage Disease Expression in Carriers
NCT02176096	Not specified	COMPLETED	Comparison of the Effect of a Novel Starch (Glycosade) Versus Gastrostomy Tube-Dextrose Infusion on Overnight Euglycaemia Control in Children With Glycogen Storage Disease Type I: Open Label Demonstration Trial
NCT02318966	Not specified	COMPLETED	Glycosade v UCCS in the Dietary Management of Hepatic GSD
NCT02338817	Not specified	TERMINATED	Clinical Evaluation of a Non-Invasive Hypoglycemia Detector in a Glycogen Storage Disease Population
NCT03255213	Not specified	COMPLETED	Lingual Muscle Training in Late-Onset Pompe Disease (LOPD)
NCT03564561	Not specified	RECRUITING	Natural History of Pompe Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04292938	Not specified	COMPLETED	McArdle Disease Treatment by Ketogenic Diet