Phosphoenolpyruvate carboxykinase deficiency

Summary

Phosphoenolpyruvate carboxykinase deficiency (MONDO:0017320) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 2
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001988	Recurrent hypoglycemia	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002173	Hypoglycemic seizures	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0003217	Hyperglutaminemia	Frequent (30-79%)
HP:0003648	Lacticaciduria	Frequent (30-79%)
HP:0012402	Increased urine alpha-ketoglutarate concentration	Frequent (30-79%)
HP:0031956	Elevated circulating aspartate aminotransferase concentration	Frequent (30-79%)
HP:0031964	Elevated circulating alanine aminotransferase concentration	Frequent (30-79%)
HP:0034648	Elevated urine fumaric acid level	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001325	Hypoglycemic coma	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0006846	Acute encephalopathy	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0001987	Hyperammonemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	phosphoenolpyruvate carboxykinase deficiency
Mondo ID	MONDO:0017320
MeSH	C536654
Orphanet	2880
ICD-11	1350463176
NCIT	C99015
SNOMED CT	5335002
UMLS	C0268194
MedGen	120618
GARD	0016613
Is cancer (heuristic)	no

Also known as: PEPCK deficiency · phosphoenolpyruvate carboxykinase (GTP) deficiency

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glucose metabolism disease › disorder of gluconeogenesis › phosphoenolpyruvate carboxykinase deficiency

Related subtypes (6): fructose-1,6-bisphosphatase deficiency, pyruvate carboxylase deficiency disease, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, glycerol kinase deficiency, infantile form, glycerol kinase deficiency, juvenile form, glycerol kinase deficiency, adult form

Subtypes (2): phosphoenolpyruvate carboxykinase deficiency, mitochondrial, phosphoenolpyruvate carboxykinase deficiency, cytosolic

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
503636	NM_004563.4(PCK2):c.1234+1G>T	PCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3780104	NM_004563.4(PCK2):c.1381del (p.Leu461fs)	NRL	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
PCK1	Strong	Autosomal recessive	phosphoenolpyruvate carboxykinase deficiency, cytosolic	3
PCK2	Supportive	Autosomal recessive	phosphoenolpyruvate carboxykinase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCK2	Orphanet:2880	Phosphoenolpyruvate carboxykinase deficiency
PCK1	Orphanet:2880	Phosphoenolpyruvate carboxykinase deficiency
NRL	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCK2	HGNC:8725	ENSG00000100889	Q16822	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial	gencc,clinvar
PCK1	HGNC:8724	ENSG00000124253	P35558	Phosphoenolpyruvate carboxykinase, cytosolic [GTP]	gencc
NRL	HGNC:8002	ENSG00000129535	P54845	Neural retina-specific leucine zipper protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCK2	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial	Mitochondrial phosphoenolpyruvate carboxykinase that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors deriv…
PCK1	Phosphoenolpyruvate carboxykinase, cytosolic [GTP]	Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis.
NRL	Neural retina-specific leucine zipper protein	Acts as a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · 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
Kinase	2	18.5×	0.008
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCK2	Kinase	yes	4.1.1.32	PEP_carboxykinase_GTP, PEP_carboxykinase_N, PEP_carboxykinase_C
PCK1	Kinase	yes	4.1.1.32	PEP_carboxykinase_GTP, PEP_carboxykinase_N, PEP_carboxykinase_C
NRL	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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
right lobe of liver	2
mucosa of transverse colon	1
small intestine Peyer’s patch	1
adult organism	1
jejunal mucosa	1
cortical plate	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCK2	172	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, small intestine Peyer’s patch
PCK1	215	tissue_specific	marker	jejunal mucosa, adult organism, right lobe of liver
NRL	129	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCK1	2,740
PCK2	2,290
NRL	937

Intra-cohort edges

A	B	Sources
PCK1	PCK2	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCK1	P35558	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCK2	Q16822	94.04
NRL	P54845	72.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gluconeogenesis	2	439.2×	3e-05	PCK2, PCK1
Abacavir metabolism	1	1427.5×	0.002	PCK1
NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis	1	1142.0×	0.002	PCK1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	190.3×	0.008	PCK1
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.016	PCK1
Interaction of NuRD complexes with transcription factors	1	63.4×	0.016	PCK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
propionate catabolic process	2	5617.3×	3e-07	PCK2, PCK1
obsolete glycerol biosynthetic process from pyruvate	2	5617.3×	3e-07	PCK2, PCK1
oxaloacetate metabolic process	2	1021.3×	1e-05	PCK2, PCK1
hepatocyte differentiation	2	802.5×	1e-05	PCK2, PCK1
cellular response to dexamethasone stimulus	2	387.4×	5e-05	PCK2, PCK1
response to starvation	2	312.1×	7e-05	PCK2, PCK1
gluconeogenesis	2	216.1×	1e-04	PCK2, PCK1
cellular response to glucose stimulus	2	178.3×	2e-04	PCK2, PCK1
cellular response to insulin stimulus	2	113.5×	4e-04	PCK2, PCK1
cellular response to potassium ion starvation	1	1872.4×	0.002	PCK1
glyceraldehyde-3-phosphate biosynthetic process	1	1404.3×	0.002	PCK1
regulation of lipid biosynthetic process	1	936.2×	0.003	PCK1
tricarboxylic acid metabolic process	1	936.2×	0.003	PCK1
pyruvate biosynthetic process	1	702.2×	0.003	PCK2
positive regulation of memory T cell differentiation	1	624.1×	0.003	PCK1
retinal rod cell development	1	561.7×	0.003	NRL
positive regulation of ferroptosis	1	510.7×	0.004	PCK2
response to acidic pH	1	432.1×	0.004	PCK1
positive regulation of lipid biosynthetic process	1	295.6×	0.006	PCK1
peptidyl-serine phosphorylation	1	165.2×	0.009	PCK1
glucose metabolic process	1	85.1×	0.016	PCK1
positive regulation of insulin secretion	1	85.1×	0.016	PCK2
response to insulin	1	77.0×	0.017	PCK1
positive regulation of transcription by RNA polymerase II	2	9.9×	0.017	NRL, PCK1
response to bacterium	1	64.6×	0.019	PCK1
cellular response to tumor necrosis factor	1	54.5×	0.022	PCK2
glucose homeostasis	1	43.5×	0.026	PCK1
response to lipopolysaccharide	1	41.6×	0.026	PCK2
visual perception	1	26.5×	0.040	NRL
positive regulation of gene expression	1	12.9×	0.078	NRL

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
PCK2	0	0
PCK1	0	0
NRL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PCK2	2	Binding:2
PCK1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCK2	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)
PCK1	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	PCK1
D	Druggable family + AlphaFold only, no drug	1	PCK2
E	Difficult family or no structure, no drug	1	NRL

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)
PCK2	2	—
PCK1	2	—
NRL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.