Hemolytic anemia due to glucophosphate isomerase deficiency

Summary

Hemolytic anemia due to glucophosphate isomerase deficiency (MONDO:0013275) is a disease caused by GPI (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GPI (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 123
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0001930	Nonspherocytic hemolytic anemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0003568	Decreased glucosephosphate isomerase level	Frequent (30-79%)
HP:0008282	Unconjugated hyperbilirubinemia	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0001082	Cholecystitis	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0004447	Poikilocytosis	Occasional (5-29%)
HP:0011981	Pigment gallstones	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hemolytic anemia due to glucophosphate isomerase deficiency
Mondo ID	MONDO:0013275
OMIM	613470
Orphanet	712
DOID	DOID:0051005
UMLS	C0272064
MedGen	543776
GARD	0016541
Is cancer (heuristic)	no

Also known as: anemia, congenital, nonspherocytic hemolytic, 4, glucose phosphate isomerase deficient · CNSHA4 · glucosephosphate isomerase deficiency · hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiency

Data availability: 123 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › hemolytic anemia due to glucophosphate isomerase deficiency

Related subtypes (9): anemia, nonspherocytic hemolytic, gamma-glutamylcysteine synthetase deficiency, glutathione synthetase deficiency without 5-oxoprolinuria, non-spherocytic hemolytic anemia due to hexokinase deficiency, hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency, pyruvate kinase deficiency of red cells, hemolytic anemia due to adenylate kinase deficiency, hemolytic anemia due to glutathione reductase deficiency, hemolytic anemia due to erythrocyte adenosine deaminase overproduction

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

123 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 14 pathogenic, 13 likely benign, 10 conflicting classifications of pathogenicity, 10 likely pathogenic, 6 benign, 4 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068750	NM_000175.5(GPI):c.286C>T (p.Arg96Ter)	GPI	Pathogenic	criteria provided, multiple submitters, no conflicts
1176072	NM_000175.5(GPI):c.1414C>T (p.Arg472Cys)	GPI	Pathogenic	criteria provided, multiple submitters, no conflicts
1323032	NM_000175.5(GPI):c.244del (p.Glu82fs)	GPI	Pathogenic	criteria provided, multiple submitters, no conflicts
1358825	NM_000175.5(GPI):c.1009G>A (p.Ala337Thr)	GPI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13640	NM_000175.5(GPI):c.1040G>A (p.Arg347His)	GPI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13642	NM_000175.5(GPI):c.1615G>A (p.Asp539Asn)	GPI	Pathogenic	criteria provided, single submitter
13644	NM_000175.5(GPI):c.59A>C (p.His20Pro)	GPI	Pathogenic	no assertion criteria provided
13645	NM_000175.5(GPI):c.1016T>C (p.Leu339Pro)	GPI	Pathogenic	no assertion criteria provided
13646	NM_000175.5(GPI):c.1028A>G (p.Gln343Arg)	GPI	Pathogenic	criteria provided, single submitter
13647	NM_000175.5(GPI):c.14C>T (p.Thr5Ile)	GPI	Pathogenic	no assertion criteria provided
13648	NM_000175.5(GPI):c.1124C>G (p.Thr375Arg)	GPI	Pathogenic	no assertion criteria provided
1679425	NM_000175.5(GPI):c.1039C>T (p.Arg347Cys)	GPI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679475	NM_000175.5(GPI):c.1144G>T (p.Glu382Ter)	GPI	Pathogenic	criteria provided, single submitter
1697237	NM_000175.5(GPI):c.301G>A (p.Val101Met)	GPI	Pathogenic	criteria provided, single submitter
2436673	NM_000175.5(GPI):c.1415G>A (p.Arg472His)	GPI	Pathogenic	criteria provided, single submitter
3339453	NC_000019.9:g.(34884972_34887205)(34893319?)del	GPI	Pathogenic	criteria provided, single submitter
3602726	NM_000175.5(GPI):c.1010C>T (p.Ala337Val)	GPI	Pathogenic	criteria provided, single submitter
504899	NM_000175.5(GPI):c.1336C>T (p.Arg446Ter)	GPI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697238	NM_000175.5(GPI):c.812del (p.Gly271fs)	GPI	Likely pathogenic	criteria provided, single submitter
2432248	NM_000175.5(GPI):c.833C>T (p.Ser278Leu)	GPI	Likely pathogenic	criteria provided, single submitter
2506149	NM_000175.5(GPI):c.1269+1G>A	GPI	Likely pathogenic	criteria provided, single submitter
2585258	NM_000175.5(GPI):c.804+1_804+2del	GPI	Likely pathogenic	criteria provided, single submitter
2690617	NM_000175.5(GPI):c.1498_1501del (p.Val500fs)	GPI	Likely pathogenic	criteria provided, single submitter
2690618	NM_000175.5(GPI):c.937_952dup (p.Val318fs)	GPI	Likely pathogenic	criteria provided, single submitter
3779707	NM_000175.5(GPI):c.48dup (p.Tyr17fs)	GPI	Likely pathogenic	criteria provided, single submitter
4081434	NM_000175.5(GPI):c.866-1G>A	GPI	Likely pathogenic	criteria provided, single submitter
4081435	NM_000175.5(GPI):c.1475-2A>G	GPI	Likely pathogenic	criteria provided, single submitter
4081436	NM_000175.5(GPI):c.1162del (p.Gln388fs)	GPI	Likely pathogenic	criteria provided, single submitter
13641	NM_000175.5(GPI):c.1574T>C (p.Ile525Thr)	GPI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13643	NM_000175.5(GPI):c.671C>T (p.Thr224Met)	GPI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
GNPDA1	Strong	Autosomal recessive	hemolytic anemia due to glucophosphate isomerase deficiency	3
GPI	Strong	Autosomal recessive	hemolytic anemia due to glucophosphate isomerase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPI	Orphanet:712	Hemolytic anemia due to glucophosphate isomerase deficiency

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
GNPDA1	HGNC:4417	ENSG00000113552	P46926	Glucosamine-6-phosphate deaminase 1	gencc,clinvar
GPI	HGNC:4458	ENSG00000105220	P06744	Glucose-6-phosphate isomerase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNPDA1	Glucosamine-6-phosphate deaminase 1	Catalyzes the reversible conversion of alpha-D-glucosamine 6-phosphate (GlcN-6P) into beta-D-fructose 6-phosphate (Fru-6P) and ammonium ion, a regulatory reaction step in de novo uridine diphosphate-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc…
GPI	Glucose-6-phosphate isomerase	Isomerase that catalyzes the conversion of alpha-D-glucose-6-phosphate to beta-D-fructose-6-phosphate, the second step in glycolysis, and the reverse reaction in gluconeogenesis, within the cytoplasm.

Protein-family classification

Druggable: 2 · 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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNPDA1	Enzyme (other)	yes	3.5.99.6	Glucosamine6P_isomerase, Glc/Gal-6P_isomerase, Glucosamine6P_isomerase_CS
GPI	Enzyme (other)	yes	5.3.1.9	G6P_Isomerase, Phosphoglucose_isomerase_CS, G6P_Isomerase_C

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
adult organism	1
nephron tubule	1
type B pancreatic cell	1
apex of heart	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNPDA1	298	ubiquitous	marker	type B pancreatic cell, nephron tubule, adult organism
GPI	286	ubiquitous	marker	apex of heart, right adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPI	4,709
GNPDA1	1,687

Intra-cohort edges

A	B	Sources
GNPDA1	GPI	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPI	P06744	13
GNPDA1	P46926	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Glycolysis	2	285.5×	5e-05	GNPDA1, GPI
Gluconeogenesis	1	219.6×	0.009	GPI
TP53 Regulates Metabolic Genes	1	64.9×	0.020	GPI
Neutrophil degranulation	1	11.5×	0.085	GPI

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
carbohydrate metabolic process	2	135.9×	0.002	GNPDA1, GPI
D-glucosamine catabolic process	1	2808.7×	0.005	GNPDA1
N-acetylglucosamine catabolic process	1	1685.2×	0.005	GNPDA1
negative regulation of glycolytic process through fructose-6-phosphate	1	1404.3×	0.005	GPI
N-acetylneuraminate catabolic process	1	1203.7×	0.005	GNPDA1
hemostasis	1	842.6×	0.005	GPI
UDP-N-acetylglucosamine biosynthetic process	1	766.0×	0.005	GNPDA1
erythrocyte homeostasis	1	648.1×	0.005	GPI
glucose 6-phosphate metabolic process	1	648.1×	0.005	GPI
fructose 6-phosphate metabolic process	1	561.7×	0.005	GPI
response to muscle stretch	1	383.0×	0.006	GPI
response to immobilization stress	1	366.4×	0.006	GPI
response to cadmium ion	1	366.4×	0.006	GPI
canonical glycolysis	1	351.1×	0.006	GPI
mesoderm formation	1	247.8×	0.007	GPI
response to progesterone	1	247.8×	0.007	GPI
positive regulation of immunoglobulin production	1	240.7×	0.007	GPI
response to testosterone	1	234.1×	0.007	GPI
glycolytic process	1	191.5×	0.008	GPI
generation of precursor metabolites and energy	1	172.0×	0.008	GNPDA1
gluconeogenesis	1	162.0×	0.009	GPI
humoral immune response	1	140.4×	0.009	GPI
positive regulation of endothelial cell migration	1	125.8×	0.010	GPI
learning or memory	1	120.4×	0.010	GPI
response to estradiol	1	99.1×	0.012	GPI
single fertilization	1	91.6×	0.012	GNPDA1
glucose homeostasis	1	65.3×	0.016	GPI
in utero embryonic development	1	36.0×	0.029	GPI
negative regulation of apoptotic process	1	17.4×	0.057	GPI

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
GNPDA1	0	0
GPI	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
GPI	2	Binding:2
GNPDA1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNPDA1	3.5.99.6	glucosamine-6-phosphate deaminase
GPI	5.3.1.9	glucose-6-phosphate isomerase

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	2	GNPDA1, GPI
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
GNPDA1	1	—
GPI	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.