GPI

glucose-6-phosphate isomerase

Basic information

Region (hg38): 19:34359480-34402413

Links

ENSG00000105220 ∙ NCBI:2821 ∙ OMIM:172400 ∙ HGNC:4458 ∙ Uniprot:P06744 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hemolytic anemia due to glucophosphate isomerase deficiency (Strong), mode of inheritance: AR
• hemolytic anemia due to glucophosphate isomerase deficiency (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemolytic anemia, nonspherocytic due to glucose phosphate isomerase deficiency	AD	Hematologic; Pharmacogenomic	Anemia may be ameliorated by splenectomy, and it may be beneficial to avoid agents (or provide monitoring if such agents are unavoidable) that may precipitate hemolytic anemia	Hematologic	5672849; 469896; 3796702; 10916680; 17041899; 20516363; 22782259

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GPI gene.

• Hemolytic anemia due to glucophosphate isomerase deficiency (10 variants)
• not provided (8 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GPI gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	19	4	24
missense	8	1	62	5	1	77
nonsense	3	1				4
start loss						0
frameshift	1	3				4
inframe indel						0
splice donor/acceptor (+/-2bp)		3				3
splice region			2	5	3	10
non coding			2	5	7	14
Total	12	8	65	29	12

Highest pathogenic variant AF is 0.0000394

Variants in GPI

This is a list of pathogenic ClinVar variants found in the GPI region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-34364916-G-A		Hemolytic anemia due to glucophosphate isomerase deficiency • GPI-related disorder	Uncertain significance (Jan 25, 2022)
19-34364991-C-T		GPI-related disorder	Likely pathogenic (Dec 24, 2023)
19-34365025-G-T		GPI-related disorder	Likely benign (Aug 09, 2019)
19-34365258-A-G		Hemolytic anemia due to glucophosphate isomerase deficiency	Uncertain significance (Apr 14, 2021)
19-34365280-C-T		Hemolytic anemia due to glucophosphate isomerase deficiency	Pathogenic (Sep 15, 1996)
19-34365282-C-T		Hemolytic anemia due to glucophosphate isomerase deficiency • Inborn genetic diseases	Uncertain significance (Jul 02, 2024)
19-34365311-A-G		GPI-related disorder	Likely benign (Nov 01, 2022)
19-34365325-A-C		Hemolytic anemia due to glucophosphate isomerase deficiency	Pathogenic (Oct 01, 1998)
19-34365353-C-T		GPI-related disorder	Likely benign (Jul 10, 2019)
19-34365357-G-C		Hemolytic anemia due to glucophosphate isomerase deficiency	Uncertain significance (Mar 14, 2022)
19-34365382-A-G		Inborn genetic diseases	Likely benign (Jun 24, 2022)
19-34365408-G-A		Hemolytic anemia due to glucophosphate isomerase deficiency	Benign (Jan 15, 2024)
19-34366375-C-T			Likely benign (May 21, 2022)
19-34366412-G-A		Hemolytic anemia due to glucophosphate isomerase deficiency	Uncertain significance (Apr 26, 2023)
19-34366771-G-A			Uncertain significance (Aug 03, 2021)
19-34366798-G-A		Inborn genetic diseases	Uncertain significance (Feb 03, 2022)
19-34366810-C-T		Hemolytic anemia due to glucophosphate isomerase deficiency	Uncertain significance (Oct 24, 2023)
19-34366810-CG-C		Hemolytic anemia due to glucophosphate isomerase deficiency	Pathogenic (Apr 21, 2022)
19-34366816-C-T			Uncertain significance (May 11, 2022)
19-34366845-C-T		GPI-related disorder	Likely benign (Mar 04, 2019)
19-34368552-G-A			Benign (Nov 12, 2018)
19-34368581-A-G		Hereditary spherocytosis	Likely pathogenic (Jun 12, 2023)
19-34368586-C-T		Hemolytic anemia due to glucophosphate isomerase deficiency	Pathogenic (Sep 01, 2021)
19-34368587-G-A		Hemolytic anemia due to glucophosphate isomerase deficiency	Uncertain significance (Jan 07, 2022)
19-34368600-C-T		GPI-related disorder	Likely benign (Mar 22, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GPI	protein_coding	protein_coding	ENST00000415930	18	42677

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000284	0.999	125684	0	64	125748	0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.13	273	331	0.825	0.0000207	3731
Missense in Polyphen		100	143.12	0.69869		1686
Synonymous	-0.0676	134	133	1.01	0.00000906	1104
Loss of Function	2.97	15	33.5	0.447	0.00000163	376

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000354	0.000354
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000201	0.000163
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000230	0.000229
Middle Eastern	0.000201	0.000163
South Asian	0.000807	0.000719
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Besides it's role as a glycolytic enzyme, mammalian GPI can function as a tumor-secreted cytokine and an angiogenic factor (AMF) that stimulates endothelial cell motility. GPI is also a neurotrophic factor (Neuroleukin) for spinal and sensory neurons. {ECO:0000269|PubMed:11004567, ECO:0000269|PubMed:11437381}.
• Disease: DISEASE: Hemolytic anemia, non-spherocytic, due to glucose phosphate isomerase deficiency (HA-GPID) [MIM:613470]: A form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency. {ECO:0000269|PubMed:7989588, ECO:0000269|PubMed:8499925, ECO:0000269|PubMed:8822952, ECO:0000269|PubMed:8822954, ECO:0000269|PubMed:9446754, ECO:0000269|PubMed:9856489}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: UDP-<i>N</i>-acetyl-D-galactosamine biosynthesis II;Glycolysis / Gluconeogenesis - Homo sapiens (human);Starch and sucrose metabolism - Homo sapiens (human);Amino sugar and nucleotide sugar metabolism - Homo sapiens (human);Pentose phosphate pathway - Homo sapiens (human);Pentose Phosphate Pathway (Erythrocyte);Glycogen synthetase deficiency;Glycogenosis, Type III. Cori disease, Debrancher glycogenosis;Mucopolysaccharidosis VI. Sly syndrome;Sucrase-isomaltase deficiency;Glycogenosis, Type IV. Amylopectinosis, Anderson disease;Glycogenosis, Type VI. Hers disease;Warburg Effect;Pentose Phosphate Pathway;Glycolysis;Glycogenosis, Type VII. Tarui disease;Gluconeogenesis;Starch and Sucrose Metabolism;Glycogenosis, Type IA. Von gierke disease;Glycogenosis, Type IC;Fanconi-bickel syndrome;Glucose-6-phosphate dehydrogenase deficiency;Ribose-5-phosphate isomerase deficiency;Glycogen Storage Disease Type 1A (GSD1A) or Von Gierke Disease;Transaldolase deficiency;Triosephosphate isomerase;Fructose-1,6-diphosphatase deficiency;Phosphoenolpyruvate carboxykinase deficiency 1 (PEPCK1);Glycogenosis, Type IB;Cori Cycle;Pathways in clear cell renal cell carcinoma;Glycolysis and Gluconeogenesis;Neutrophil degranulation;Gene expression (Transcription);Generic Transcription Pathway;Metabolism of carbohydrates;Fructose Mannose metabolism;Glycolysis Gluconeogenesis;RNA Polymerase II Transcription;Glycolysis and Gluconeogenesis;Innate Immune System;Immune System;Metabolism;Pentose phosphate cycle;TP53 Regulates Metabolic Genes;Glycolysis;gluconeogenesis;GDP-mannose biosynthesis;Transcriptional Regulation by TP53;glycolysis;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Gluconeogenesis;Glucose metabolism (Consensus)

Recessive Scores

• pRec: 0.859

Intolerance Scores

• loftool: 0.0584
• rvis_EVS: -0.91
• rvis_percentile_EVS: 10.03

Haploinsufficiency Scores

• pHI: 0.367
• hipred: Y
• hipred_score: 0.674
• ghis: 0.571

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.932

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gpi1
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; embryo phenotype; liver/biliary system phenotype; respiratory system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); immune system phenotype

Gene ontology

• Biological process: in utero embryonic development;mesoderm formation;carbohydrate metabolic process;gluconeogenesis;glycolytic process;humoral immune response;hemostasis;learning or memory;regulation of signaling receptor activity;positive regulation of endothelial cell migration;methylglyoxal biosynthetic process;response to estradiol;response to progesterone;response to testosterone;erythrocyte homeostasis;response to immobilization stress;response to muscle stretch;glucose homeostasis;negative regulation of cysteine-type endopeptidase activity involved in apoptotic process;response to morphine;neutrophil degranulation;negative regulation of neuron apoptotic process;aldehyde catabolic process;response to cadmium ion;positive regulation of immunoglobulin secretion;glucose 6-phosphate metabolic process;canonical glycolysis
• Cellular component: extracellular region;nucleoplasm;cytosol;plasma membrane;membrane;secretory granule lumen;neuron projection;myelin sheath;ciliary membrane;extracellular exosome;ficolin-1-rich granule lumen
• Molecular function: glucose-6-phosphate isomerase activity;cytokine activity;growth factor activity;intramolecular transferase activity;ubiquitin protein ligase binding;monosaccharide binding