PCK1

protein-coding

phosphoenolpyruvate carboxykinase 1

Gene summary

This gene is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of cytosolic phosphoenolpyruvate carboxykinase deficiency. A mitochondrial isozyme of the encoded protein also has been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002591.4

Inheritance

ClinVar variants

P:14U:152B:94

Top phenotype

Phosphoenolpyruvate carboxykinase-1 deficiency, cytosolic

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr20:57,561,080-57,568,121

External References & Databases

Ensembl (ENSG00000124253)

Transcript & Mutation Effects

hg38 • Region Span ~7.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

phosphoenolpyruvate carboxykinase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017320

Submitter: Orphanet

phosphoenolpyruvate carboxykinase deficiency, cytosolicSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009866

Submitter: Labcorp Genetics (formerly Invitae)

phosphoenolpyruvate carboxykinase deficiency, cytosolicDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009866

Submitter: ClinGen

PCK1 encodes the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) that is the rate-limiting enzyme in gluconeogenesis and crucial for cataplerosis. This isoform is highly expressed in the liver and accounts for approximately 50% of total PEPCK activity. PCK1 variants were first reported in association with autosomal recessive PEPCK-C deficiency in 2014 (Adam et al., PMID: 24863970). The primary features include fasting or illness associated episodic hypoglycemia, lactic and/or metabolic acidosis, elevated lactate and tricarboxylic acid (TCA) cycle intermediates, and, in some cases, liver involvement such as steatosis and hepatic inflammation. Clinical presentation and disease severity are highly variable. Eight PCK1 variants (including missense, in-frame deletion, frameshift, and splicing variants) have been reported in eight probands across five publications (PMIDs: 24863970, 26971250, 35868242, 37924129, 40092582) and are included in this curation. In addition, a homozygous missense variant, c.925G>A (p.Gly309Arg), reported as a founder mutation in the Finnish population, has been identified in 16 unrelated probands (PMIDs: 28216384, 34622459). The proposed mechanism of pathogenicity is biallelic loss of function. This gene–disease relationship is further supported by experimental evidence. Whole-body PCK1 knockout (KO) mice exhibit hypoglycemia, elevated malate and lactate levels, hepatic lipid accumulation, and early death (PMID: 16300682). Both hypoglycemia and lifespan were partially rescued by adenovirus mediated PCK1 delivery in the liver of KO mice (PMID: 27785616). Studies of patient liver tissue and transfected cell models demonstrate reduced PEPCK-C protein levels and enzymatic activity, likely due to increased protein instability, as evidenced by time-dependent protein degradation (PMIDs: 24863970, 28216384, 26971250). In summary, there is definitive evidence supporting the relationship between PCK1 and autosomal recessive PEPCK-C deficiency. This relationship has demonstrated in both research and clinical diagnostic settings and remains consistent over time. This classification was approved by the ClinGen IEM GCEP on April 24, 2026 (SOP Version 12).

phosphoenolpyruvate carboxykinase deficiency, cytosolicSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009866

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Phosphoenolpyruvate carboxykinase-1 deficiency, cytosolicAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: Individuals have been described with manifestations such as early-onset hypoglycemia, and awareness can allow prompt treatment of acute episodes as well as longer-term dietary management (low-fat, high-carbohydrate diet with frequent feedings)

Refs: 24863970; 26971250; 28216384

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCK1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 158

Inborn genetic diseasesTotal: 103

Phosphoenolpyruvate carboxykinase deficiency, cytosolicTotal: 55

not specifiedTotal: 24

PCK1-related disorderTotal: 23

Inborn errors of metabolismTotal: 2

Lynch syndrome 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002591.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	75 clinvar	4 clinvar	84
missense	1 clinvar	4 clinvar	137 clinvar	14 clinvar	1 clinvar	157
nonsense	1 clinvar	2 clinvar	2 clinvar			5
start loss						0
frameshift	1 clinvar	3 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	6 clinvar			8
Total	4	10	152	89	5	260

Highest pathogenic variant AF is 0.00059007364

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002591.4	RefSeq	NP_002582.3	9	MANE Select
ENST00000319441.6	Ensembl	ENSP00000319814.4	9	MANE Select
ENST00000851908.1	Ensembl	ENSP00000521967.1	9	Standard
ENST00000851908.2	Ensembl	ENSP00000521967.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pck1	Danio rerio	Structure: glucose homeostasis Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

pck1

Danio rerio

Structure: glucose homeostasis

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Citrate cycle (TCA cycle) - Homo sapiens (human)
Pyruvate metabolism - Homo sapiens (human)
Adipocytokine signaling pathway - Homo sapiens (human)
Glycolysis / Gluconeogenesis - Homo sapiens (human)

Biological Process

glucose metabolic process
pyruvate metabolic process
gluconeogenesis
oxaloacetate metabolic process
internal protein amino acid acetylation

Molecular Function

magnesium ion binding
phosphoenolpyruvate carboxykinase (GTP) activity
GTP binding
GDP binding
manganese ion binding

Cellular Component

cytoplasm
mitochondrion
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319441
Coding exons: 9
Length: 5378
Individuals with no LoFs: 125666
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125748
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0430	386	384	1.01	0.0000227	4114
Missense (PolyPhen)		165	180.31	0.91511		1846
Synonymous	-1.28	182	161	1.13	0.0000111	1192
Loss of Function	0.427	23	25.3	0.909	0.00000108	296

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00043	0.00043	rare
South Asian	0.00043	0.00042	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 derived from the citric acid cycle. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384}.;
Disease: DISEASE: Phosphoenolpyruvate carboxykinase deficiency, cytosolic (PCKDC) [MIM:261680]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, hypoglycemia, hypotonia, hepatomegaly, hepatic dysfunction, failure to thrive, lactic acidosis, and elevated tricarboxylic acid intermediates, particularly fumarate, in urine. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.502

Intolerance Scores

LoFtool: 0.718
RVIS EVS: 0.28
RVIS percentile EVS: 70.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium