Phosphoenolpyruvate carboxykinase deficiency, cytosolic

Summary

Phosphoenolpyruvate carboxykinase deficiency, cytosolic (MONDO:0009866) is a disease caused by PCK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PCK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 84

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	phosphoenolpyruvate carboxykinase deficiency, cytosolic
Mondo ID	MONDO:0009866
OMIM	261680
Orphanet	79316
UMLS	C5574905
MedGen	1801754
GARD	0004278
Is cancer (heuristic)	no

Also known as: PCKDC · PEP carboxykinase deficiency · PEPCK 1 deficiency · phosphoenolpyruvate carboxykinase deficiency · phosphoenolpyruvate carboxykinase deficiency, cytosolic · phosphoenolpyruvate carboxykinase-1 (PCK1) deficiency · phosphoenolpyruvate carboxylase deficiency · phosphopyruvate carboxylase deficiency

Data availability: 84 ClinVar variants · 2 GenCC gene-disease records.

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, cytosolic

Related subtypes (1): phosphoenolpyruvate carboxykinase deficiency, mitochondrial

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

84 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 20 conflicting classifications of pathogenicity, 17 benign, 5 benign/likely benign, 3 likely benign, 3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2502278	NM_002591.4(PCK1):c.574T>C (p.Cys192Arg)	PCK1	Pathogenic	no assertion criteria provided
440852	PCK1, 12-BP DEL, NT369	PCK1	Pathogenic	no assertion criteria provided
3767977	NM_002591.4(PCK1):c.705C>G (p.Tyr235Ter)	PCK1	Likely pathogenic	criteria provided, single submitter
4849447	NM_002591.4(PCK1):c.1299dup (p.Gly434fs)	PCK1	Likely pathogenic	criteria provided, single submitter
931905	NM_002591.4(PCK1):c.961+1G>A	PCK1	Likely pathogenic	criteria provided, single submitter
1474811	NM_002591.4(PCK1):c.1268C>T (p.Pro423Leu)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338869	NM_002591.4(PCK1):c.102C>T (p.Asn34=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338870	NM_002591.4(PCK1):c.141C>T (p.Asp47=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338880	NM_002591.4(PCK1):c.556G>A (p.Asp186Asn)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338885	NM_002591.4(PCK1):c.898C>T (p.Leu300Phe)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338886	NM_002591.4(PCK1):c.925G>A (p.Gly309Arg)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338887	NM_002591.4(PCK1):c.954C>T (p.Asp318=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338891	NM_002591.4(PCK1):c.1642G>A (p.Ala548Thr)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338892	NM_002591.4(PCK1):c.1644C>G (p.Ala548=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707924	NM_002591.4(PCK1):c.1152G>A (p.Thr384=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
743838	NM_002591.4(PCK1):c.858C>T (p.Ser286=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779639	NM_002591.4(PCK1):c.1448G>A (p.Arg483Gln)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
788182	NM_002591.4(PCK1):c.7C>T (p.Pro3Ser)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
789357	NM_002591.4(PCK1):c.413C>T (p.Thr138Ile)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807457	NM_002591.4(PCK1):c.724G>A (p.Gly242Arg)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895818	NM_002591.4(PCK1):c.747G>A (p.Arg249=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896100	NM_002591.4(PCK1):c.903C>T (p.Pro301=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897622	NM_002591.4(PCK1):c.414C>A (p.Thr138=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898782	NM_002591.4(PCK1):c.474C>T (p.Ile158=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898848	NM_002591.4(PCK1):c.1320T>C (p.Gly440=)	PCK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338866	NM_002591.4(PCK1):c.-64C>T	PCK1	Uncertain significance	criteria provided, single submitter
338867	NM_002591.4(PCK1):c.-54C>T	PCK1	Uncertain significance	criteria provided, single submitter
338872	NM_002591.4(PCK1):c.203G>T (p.Arg68Leu)	PCK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
338878	NM_002591.4(PCK1):c.538G>A (p.Val180Ile)	PCK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
338890	NM_002591.4(PCK1):c.1207A>G (p.Asn403Asp)	PCK1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCK1	Orphanet:2880	Phosphoenolpyruvate carboxykinase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCK1	HGNC:8724	ENSG00000124253	P35558	Phosphoenolpyruvate carboxykinase, cytosolic [GTP]	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCK1	Kinase	yes	4.1.1.32	PEP_carboxykinase_GTP, PEP_carboxykinase_N, PEP_carboxykinase_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult organism	1
jejunal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCK1	215	tissue_specific	marker	jejunal mucosa, adult organism, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCK1	2,740

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCK1	P35558	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
Abacavir metabolism	1	2855.0×	0.001	PCK1
NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis	1	2284.0×	0.001	PCK1
Gluconeogenesis	1	439.2×	0.004	PCK1
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.004	PCK1
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.008	PCK1
Interaction of NuRD complexes with transcription factors	1	126.9×	0.008	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 1 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	8426.0×	0.001	PCK1
obsolete glycerol biosynthetic process from pyruvate	1	8426.0×	0.001	PCK1
cellular response to potassium ion starvation	1	5617.3×	0.001	PCK1
glyceraldehyde-3-phosphate biosynthetic process	1	4213.0×	0.001	PCK1
regulation of lipid biosynthetic process	1	2808.7×	0.001	PCK1
tricarboxylic acid metabolic process	1	2808.7×	0.001	PCK1
positive regulation of memory T cell differentiation	1	1872.4×	0.002	PCK1
oxaloacetate metabolic process	1	1532.0×	0.002	PCK1
response to acidic pH	1	1296.3×	0.002	PCK1
hepatocyte differentiation	1	1203.7×	0.002	PCK1
positive regulation of lipid biosynthetic process	1	887.0×	0.002	PCK1
cellular response to dexamethasone stimulus	1	581.1×	0.003	PCK1
peptidyl-serine phosphorylation	1	495.6×	0.003	PCK1
response to starvation	1	468.1×	0.003	PCK1
gluconeogenesis	1	324.1×	0.005	PCK1
cellular response to glucose stimulus	1	267.5×	0.005	PCK1
glucose metabolic process	1	255.3×	0.005	PCK1
response to insulin	1	230.8×	0.005	PCK1
response to bacterium	1	193.7×	0.006	PCK1
cellular response to insulin stimulus	1	170.2×	0.006	PCK1
glucose homeostasis	1	130.6×	0.008	PCK1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	PCK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCK1	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
PCK1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCK1	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCK1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.