glycogen storage disease IXa1

Summary

glycogen storage disease IXa1 (MONDO:0010598) is a disease caused by PHKA2 (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Causal gene: PHKA2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 433
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease IXa1
Mondo ID	MONDO:0010598
MeSH	C564421, D006015
OMIM	306000
DOID	DOID:0111042, DOID:2751
SNOMED CT	41527003
UMLS	C3694531
MedGen	854172
GARD	0018386
MedDRA	10053242
Is cancer (heuristic)	no

Also known as: glycogen storage disease 8 · glycogen storage disease caused by mutation in PHKA2 · glycogen storage disease IXa · glycogen storage disease IXa1 · glycogen storage disease type 9A · glycogen storage disease type IXa · glycogen storage disease type VIII · glycogen storage disease VIII · glycogen storage disease, type IXa1, X-linked recessive · glycogen storage disease, type IXa2, X-linked recessive · glycogenosis type 8 · glycogenosis type 9A · glycogenosis type IXa · GSD9A1 · hepatic phosphorylase kinase deficiency · PHKA2 glycogen storage disease · PHKA2-related glycogen storage disease type IX · phosphorylase kinase deficiency of liver · PYKL

Data availability: 433 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disease due to liver phosphorylase kinase deficiency › glycogen storage disease IXa1

Related subtypes (1): glycogen storage disease IXc

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

433 retrieved; paginated sample, class counts are floors:

138 likely benign, 121 uncertain significance, 51 pathogenic, 38 likely pathogenic, 27 conflicting classifications of pathogenicity, 23 benign, 23 benign/likely benign, 12 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1006299	NM_000292.3(PHKA2):c.2470C>T (p.Arg824Cys)	PHKA2	Pathogenic	criteria provided, single submitter
1013871	NM_000292.3(PHKA2):c.4C>G (p.Arg2Gly)	PHKA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1026764	NM_000292.3(PHKA2):c.893G>C (p.Arg298Pro)	PHKA2	Pathogenic	criteria provided, single submitter
1028673	NM_000292.3(PHKA2):c.3529C>T (p.Gln1177Ter)	PHKA2	Pathogenic	criteria provided, single submitter
10527	NM_000292.3(PHKA2):c.3025C>T (p.Gln1009Ter)	PHKA2	Pathogenic	no assertion criteria provided
10528	NM_000292.3(PHKA2):c.2296C>T (p.Gln766Ter)	PHKA2	Pathogenic	no assertion criteria provided
10529	NM_000292.3(PHKA2):c.717+1G>T	PHKA2	Pathogenic	no assertion criteria provided
10530	NM_000292.3(PHKA2):c.3146C>A (p.Ser1049Ter)	PHKA2	Pathogenic	no assertion criteria provided
10531	NM_000292.3(PHKA2):c.3614C>T (p.Pro1205Leu)	PHKA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10532	NM_000292.3(PHKA2):c.421_423del (p.Phe141del)	PHKA2	Pathogenic	no assertion criteria provided
10534	NM_000292.3(PHKA2):c.896A>G (p.Asp299Gly)	PHKA2	Pathogenic	no assertion criteria provided
10536	NM_000292.3(PHKA2):c.395A>C (p.His132Pro)	PHKA2	Pathogenic	criteria provided, single submitter
10537	NM_000292.3(PHKA2):c.394C>T (p.His132Tyr)	PHKA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067758	NM_000292.3(PHKA2):c.1A>G (p.Met1Val)	PHKA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071224	NM_000292.3(PHKA2):c.3325del (p.Thr1109fs)	PHKA2	Pathogenic	criteria provided, single submitter
1072784	NM_000292.3(PHKA2):c.2378_2379del (p.Thr793fs)	PHKA2	Pathogenic	criteria provided, single submitter
1333453	NM_000292.3(PHKA2):c.256C>T (p.Arg86Ter)	PHKA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456672	NM_000292.3(PHKA2):c.2614G>T (p.Glu872Ter)	PHKA2	Pathogenic	criteria provided, single submitter
1459330	NM_000292.3(PHKA2):c.2509_2510insATGTATAAATATGTAACTAACCTGCACAATGTGCACATGTACCCTAAAACTTATATTATAATAAAAAAAAAAAAAAAAAAATAACAATAAAATGAGATAAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAGTGGAGGTCC (p.Leu837delinsHisValTer)	PHKA2	Pathogenic	criteria provided, single submitter
1686059	NM_000292.3(PHKA2):c.1324+1G>A	PHKA2	Pathogenic	criteria provided, single submitter
1686060	NM_000292.3(PHKA2):c.1210C>T (p.Gln404Ter)	PHKA2	Pathogenic	criteria provided, single submitter
1703196	NM_000292.3(PHKA2):c.892C>T (p.Arg298Ter)	PHKA2	Pathogenic	criteria provided, single submitter
1810400	NM_000292.3(PHKA2):c.1969C>T (p.Gln657Ter)	PHKA2	Pathogenic	criteria provided, single submitter
208493	NM_000292.3(PHKA2):c.883C>T (p.Arg295Cys)	PHKA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2101957	NM_000292.3(PHKA2):c.1420C>T (p.Gln474Ter)	PHKA2	Pathogenic	criteria provided, single submitter
2138484	NM_000292.3(PHKA2):c.1174C>T (p.Arg392Ter)	PHKA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2422823	NC_000023.10:g.(?18925998)(18929098_?)del	PHKA2	Pathogenic	criteria provided, single submitter
2696072	NM_000292.3(PHKA2):c.3329_3336+6del	PHKA2	Pathogenic	criteria provided, single submitter
2700165	NM_000292.3(PHKA2):c.2783_2793del (p.Leu928fs)	PHKA2	Pathogenic	criteria provided, single submitter
2767520	NM_000292.3(PHKA2):c.1502del (p.His501fs)	PHKA2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PHKA2	Definitive	X-linked	glycogen storage disease IXa1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHKA2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency
ADGRG2	Orphanet:48	Congenital bilateral absence of vas deferens

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PHKA2	HGNC:8926	ENSG00000044446	P46019	Phosphorylase b kinase regulatory subunit alpha, liver isoform	gencc,clinvar
PHKA2-AS1	HGNC:44110	ENSG00000237836		PHKA2 antisense RNA 1	clinvar
ADGRG2	HGNC:4516	ENSG00000173698	Q8IZP9	Adhesion G-protein coupled receptor G2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PHKA2	Phosphorylase b kinase regulatory subunit alpha, liver isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
ADGRG2	Adhesion G-protein coupled receptor G2	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	8.0×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PHKA2	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PHKA2-AS1	Other/Unknown	no
ADGRG2	GPCR	yes		GPS, GPCR_2_secretin-like, GPCR_2-like_7TM

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right lobe of liver	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
right adrenal gland	1
right adrenal gland cortex	1
caput epididymis	1
corpus epididymis	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHKA2	266	ubiquitous	marker	right lobe of liver, right uterine tube, apex of heart
PHKA2-AS1	131		yes	male germ line stem cell (sensu Vertebrata) in testis, right adrenal gland, right adrenal gland cortex
ADGRG2	182	broad	marker	corpus epididymis, caput epididymis, parotid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHKA2	1,070
ADGRG2	723
PHKA2-AS1	0

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHKA2	P46019	81.36
ADGRG2	Q8IZP9	62.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen metabolism	1	1903.3×	0.002	PHKA2
Glycogen breakdown (glycogenolysis)	1	761.3×	0.003	PHKA2
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.011	PHKA2
Metabolism	1	11.6×	0.086	PHKA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen metabolic process	1	263.3×	0.025	PHKA2
generation of precursor metabolites and energy	1	172.0×	0.025	PHKA2
protein modification process	1	122.1×	0.025	PHKA2
spermatid development	1	72.6×	0.025	ADGRG2
carbohydrate metabolic process	1	68.0×	0.025	PHKA2
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.025	ADGRG2
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.025	ADGRG2
cell surface receptor signaling pathway	1	32.0×	0.039	ADGRG2
G protein-coupled receptor signaling pathway	1	18.1×	0.056	ADGRG2
spermatogenesis	1	17.6×	0.056	ADGRG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHKA2	0	0
PHKA2-AS1	0	0
ADGRG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PHKA2	48	Binding:48
ADGRG2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHKA2	2.7.11.19	phosphorylase kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	PHKA2, ADGRG2
E	Difficult family or no structure, no drug	1	PHKA2-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PHKA2	48	—
PHKA2-AS1	0	—
ADGRG2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04454216	Not specified	RECRUITING	GSD VI and GSD IX Natural History
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)