Phosphoenolpyruvate carboxykinase deficiency, mitochondrial

Summary

Phosphoenolpyruvate carboxykinase deficiency, mitochondrial (MONDO:0009864) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	phosphoenolpyruvate carboxykinase deficiency, mitochondrial
Mondo ID	MONDO:0009864
MeSH	C564890
OMIM	261650
Orphanet	79317
UMLS	C1849821
MedGen	376665
GARD	0004279
Is cancer (heuristic)	no

Also known as: PCKDM · PEPCK 2 deficiency · PEPCK deficiency, mitochondrial · PEPCK2 · phosphoenolpyruvate carboxykinase 2 deficiency · phosphoenolpyruvate carboxykinase deficiency, mitochondrial

Data availability: 15 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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

Related subtypes (1): 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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 6 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4849279	NM_004563.4(PCK2):c.652_653del (p.Leu218fs)	NRL	Likely pathogenic	criteria provided, single submitter
374449	NM_004563.4(PCK2):c.68C>G (p.Ser23Ter)	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383754	NM_004563.4(PCK2):c.1405C>T (p.Arg469Cys)	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3891919	NM_004563.4(PCK2):c.1018C>T (p.Arg340Ter)	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440999	NM_004563.4(PCK2):c.1468+2T>C	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618263	NM_004563.4(PCK2):c.1756G>A (p.Gly586Ser)	NRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451808	NM_004563.4(PCK2):c.577C>T (p.Arg193Ter)	PCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030819	NM_004563.4(PCK2):c.1907G>A (p.Arg636His)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032911	NM_004563.4(PCK2):c.287G>A (p.Arg96His)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032912	NM_004563.4(PCK2):c.157C>T (p.Arg53Cys)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1432827	NM_004563.4(PCK2):c.424C>T (p.Arg142Ter)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2723891	NM_004563.4(PCK2):c.1906C>T (p.Arg636Cys)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2884023	NM_004563.4(PCK2):c.820C>T (p.Arg274Trp)	NRL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1686014	NM_004563.4(PCK2):c.460_461insCTGTGGATGAGAG (p.Gly154fs)	PCK2	Uncertain significance	criteria provided, single submitter
720616	NM_004563.4(PCK2):c.1469-3dup	NRL	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
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
NRL	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCK2	HGNC:8725	ENSG00000100889	Q16822	Phosphoenolpyruvate carboxykinase [GTP], mitochondrial	gencc,clinvar
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…
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: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	1	13.9×	0.142
Transcription factor	1	4.1×	0.228

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
NRL	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
right lobe of liver	1
small intestine Peyer’s patch	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
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: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCK2	2,290
NRL	937

Structural data

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

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: 1. Enrichment computed across 2 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
Gluconeogenesis	1	439.2×	0.002	PCK2

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
propionate catabolic process	1	4213.0×	0.002	PCK2
obsolete glycerol biosynthetic process from pyruvate	1	4213.0×	0.002	PCK2
pyruvate biosynthetic process	1	1053.2×	0.004	PCK2
retinal rod cell development	1	842.6×	0.004	NRL
oxaloacetate metabolic process	1	766.0×	0.004	PCK2
positive regulation of ferroptosis	1	766.0×	0.004	PCK2
hepatocyte differentiation	1	601.9×	0.005	PCK2
cellular response to dexamethasone stimulus	1	290.6×	0.008	PCK2
response to starvation	1	234.1×	0.009	PCK2
gluconeogenesis	1	162.0×	0.012	PCK2
cellular response to glucose stimulus	1	133.8×	0.012	PCK2
positive regulation of insulin secretion	1	127.7×	0.012	PCK2
cellular response to insulin stimulus	1	85.1×	0.017	PCK2
cellular response to tumor necrosis factor	1	81.8×	0.017	PCK2
response to lipopolysaccharide	1	62.4×	0.020	PCK2
visual perception	1	39.8×	0.030	NRL
positive regulation of gene expression	1	19.4×	0.057	NRL
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	NRL
regulation of transcription by RNA polymerase II	1	5.8×	0.164	NRL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
NRL	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
PCK2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCK2	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)

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	1	PCK2
E	Difficult family or no structure, no drug	1	NRL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCK2	2	—
NRL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.