anemia, nonspherocytic hemolytic, due to G6PD deficiency

Summary

anemia, nonspherocytic hemolytic, due to G6PD deficiency (MONDO:0010480) is a disease caused by G6PD (GenCC Definitive), with 6 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: G6PD (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 761

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	anemia, nonspherocytic hemolytic, due to G6PD deficiency
Mondo ID	MONDO:0010480
MeSH	C567533
OMIM	300908
Orphanet	466026
DOID	DOID:0051003
UMLS	C2720289
MedGen	403555
GARD	0006520
Is cancer (heuristic)	no

Also known as: anemia, congenital, nonspherocytic hemolytic, 1, G6PD deficient · anemia, nonspherocytic hemolytic, due to G6PD deficiency · Class I G6PD deficiency · class I glucose-6-phosphate dehydrogenase deficiency · hemolytic anaemia due to G6PD deficiency · hemolytic anemia due to G6PD deficiency · hemolytic anemia, G6PD deficient (favism), X-linked dominant · severe hemolytic anaemia due to G6PD deficiency · severe hemolytic anemia due to G6PD deficiency

Data availability: 761 ClinVar variants · 3 GenCC gene-disease records · 21 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › anemia, nonspherocytic hemolytic › anemia, nonspherocytic hemolytic, due to G6PD deficiency

Related subtypes (2): anemia, nonspherocytic hemolytic, associated with abnormality of red cell membrane, anemia, nonspherocytic hemolytic, possibly due to defect in porphyrin metabolism

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

600 retrieved; paginated sample, class counts are floors:

234 likely benign, 124 likely pathogenic, 91 uncertain significance, 62 pathogenic, 39 conflicting classifications of pathogenicity, 32 pathogenic/likely pathogenic, 14 benign, 3 benign/likely benign, 1 likely pathogenic/established risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065168	NM_001360016.2(G6PD):c.[376A>G;968T>C]		Pathogenic	criteria provided, multiple submitters, no conflicts
3243728	NC_000023.10:g.(?152954030)(154005142_?)del	ABCD1	Pathogenic	criteria provided, single submitter
1343138	NM_001367721.1(CASK):c.2317+5G>A	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100057	NM_000402.4(G6PD):c.653C>T (p.Ser218Phe)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100058	NM_000402.4(G6PD):c.1466G>T (p.Arg489Leu)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
100059	NM_000402.4(G6PD):c.1478G>A (p.Arg493His)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10362	NM_000402.4(G6PD):c.944G>A (p.Arg315His)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10363	NM_000402.4(G6PD):c.1093G>A (p.Ala365Thr)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10367	NM_000402.4(G6PD):c.577G>A (p.Gly193Ser)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10370	NM_000402.4(G6PD):c.1268G>A (p.Arg423His)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10371	NM_000402.4(G6PD):c.1429G>A (p.Gly477Arg)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10372	NM_000402.4(G6PD):c.934G>C (p.Asp312His)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10375	NM_000402.4(G6PD):c.1246A>G (p.Lys416Glu)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10376	NM_000402.4(G6PD):c.1250G>A (p.Arg417His)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10377	NM_000402.4(G6PD):c.1243T>C (p.Cys415Arg)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10378	NM_000402.4(G6PD):c.1318G>T (p.Gly440Cys)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10379	NM_000402.4(G6PD):c.1451G>A (p.Arg484His)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10381	NM_000402.4(G6PD):c.1192G>A (p.Glu398Lys)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10383	NM_000402.4(G6PD):c.727G>T (p.Val243Leu)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10385	NM_000402.4(G6PD):c.1147C>T (p.Pro383Ser)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10386	NM_000402.4(G6PD):c.961G>A (p.Val321Met)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10388	NM_001360016.2(G6PD):c.968T>C (p.Leu323Pro)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10391	NM_000402.4(G6PD):c.682C>T (p.Arg228Cys)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10393	NM_000402.4(G6PD):c.583A>G (p.Asn195Asp)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10396	NM_000402.4(G6PD):c.1249C>T (p.Arg417Cys)	G6PD	Pathogenic	criteria provided, multiple submitters, no conflicts
10398	NM_000402.4(G6PD):c.1319G>A (p.Gly440Asp)	G6PD	Pathogenic	criteria provided, single submitter
10401	NM_000402.4(G6PD):c.1039G>A (p.Glu347Lys)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10402	NM_000402.4(G6PD):c.233T>C (p.Ile78Thr)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10403	NM_000402.4(G6PD):c.185A>G (p.His62Arg)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10404	NM_000402.4(G6PD):c.482G>T (p.Gly161Val)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · 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
G6PD	Definitive	X-linked	anemia, nonspherocytic hemolytic, due to G6PD deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
G6PD	Orphanet:466026	Class I glucose-6-phosphate dehydrogenase deficiency
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
LAGE3	Orphanet:2065	Galloway-Mowat syndrome
GFI1	Orphanet:486	Autosomal dominant severe congenital neutropenia
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
G6PD	HGNC:4057	ENSG00000160211	P11413	Glucose-6-phosphate 1-dehydrogenase	gencc,clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
LAGE3	HGNC:26058	ENSG00000196976	Q14657	EKC/KEOPS complex subunit LAGE3	clinvar
DUSP9	HGNC:3076	ENSG00000130829	Q99956	Dual specificity protein phosphatase 9	clinvar
GFI1	HGNC:4237	ENSG00000162676	Q99684	Zinc finger protein Gfi-1	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
G6PD	Glucose-6-phosphate 1-dehydrogenase	Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
LAGE3	EKC/KEOPS complex subunit LAGE3	Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine.
DUSP9	Dual specificity protein phosphatase 9	Inactivates MAP kinases.
GFI1	Zinc finger protein Gfi-1	Transcription repressor essential for hematopoiesis.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.67

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
Phosphatase	1	14.0×	0.224
Transporter	1	13.0×	0.224
Kinase	1	4.6×	0.396
Enzyme (other)	1	2.0×	0.610
Transcription factor	1	1.4×	0.647
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
G6PD	Enzyme (other)	yes	1.1.1.49	G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
LAGE3	Other/Unknown	no		CTAG/Pcc1
DUSP9	Phosphatase	yes	3.1.3.48	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Rhodanese-like_dom
GFI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
right testis	1
stromal cell of endometrium	1
buccal mucosa cell	1
cortical plate	1
hair follicle	1
Brodmann (1909) area 10	1
oocyte	1
secondary oocyte	1
adult mammalian kidney	1
placenta	1
renal medulla	1
bone marrow	1
bone marrow cell	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
G6PD	218	ubiquitous	marker	stromal cell of endometrium, granulocyte, right testis
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
LAGE3	273	ubiquitous	marker	oocyte, secondary oocyte, Brodmann (1909) area 10
DUSP9	107	broad	marker	placenta, renal medulla, adult mammalian kidney
GFI1	153	broad	yes	granulocyte, bone marrow, bone marrow cell
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
G6PD	4,226
CASK	4,223
GFI1	2,148
DUSP9	1,500
ABCD1	1,181
LAGE3	870

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
G6PD	P11413	25
CASK	O14936	22
ABCD1	P33897	14
LAGE3	Q14657	2
DUSP9	Q99956	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GFI1	Q99684	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	951.7×	0.030	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	317.2×	0.030	ABCD1
Signaling by MAPK mutants	1	271.9×	0.030	DUSP9
NFE2L2 regulates pentose phosphate pathway genes	1	237.9×	0.030	G6PD
Linoleic acid (LA) metabolism	1	190.3×	0.030	ABCD1
Pentose phosphate pathway	1	158.6×	0.030	G6PD
Beta-oxidation of very long chain fatty acids	1	146.4×	0.030	ABCD1
alpha-linolenic acid (ALA) metabolism	1	119.0×	0.030	ABCD1
Peroxisomal lipid metabolism	1	112.0×	0.030	ABCD1
RAF-independent MAPK1/3 activation	1	105.7×	0.030	DUSP9
ABC transporters in lipid homeostasis	1	100.2×	0.030	ABCD1
Class I peroxisomal membrane protein import	1	86.5×	0.030	ABCD1
Dopamine Neurotransmitter Release Cycle	1	82.8×	0.030	CASK
Nephrin family interactions	1	79.3×	0.030	CASK
ABC transporter disorders	1	73.2×	0.030	ABCD1
Syndecan interactions	1	70.5×	0.030	CASK
tRNA processing	1	59.5×	0.033	LAGE3
tRNA modification in the nucleus and cytosol	1	48.8×	0.038	LAGE3
Negative regulation of MAPK pathway	1	44.3×	0.040	DUSP9
Assembly and cell surface presentation of NMDA receptors	1	42.3×	0.040	CASK
Sensory processing of sound by outer hair cells of the cochlea	1	34.0×	0.046	CASK
Neurexins and neuroligins	1	32.8×	0.046	CASK
Protein localization	1	31.7×	0.046	ABCD1
Sensory processing of sound by inner hair cells of the cochlea	1	27.2×	0.051	CASK
Disorders of transmembrane transporters	1	23.2×	0.057	ABCD1
Fatty acid metabolism	1	21.9×	0.057	ABCD1
TP53 Regulates Metabolic Genes	1	21.6×	0.057	G6PD
Transcriptional regulation of granulopoiesis	1	20.9×	0.057	GFI1
ABC-family protein mediated transport	1	20.2×	0.057	ABCD1
Metabolism of RNA	1	7.0×	0.154	LAGE3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ribose phosphate biosynthetic process	1	2808.7×	0.008	G6PD
response to iron(III) ion	1	1404.3×	0.008	G6PD
peroxisomal membrane transport	1	1404.3×	0.008	ABCD1
pentose biosynthetic process	1	1404.3×	0.008	G6PD
very long-chain fatty-acyl-CoA catabolic process	1	1404.3×	0.008	ABCD1
negative regulation of cellular response to growth factor stimulus	1	1404.3×	0.008	CASK
positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	1404.3×	0.008	G6PD
positive regulation of interleukin-6-mediated signaling pathway	1	936.2×	0.009	GFI1
positive regulation of unsaturated fatty acid biosynthetic process	1	936.2×	0.009	ABCD1
pentose-phosphate shunt, oxidative branch	1	702.2×	0.009	G6PD
negative regulation of vitamin D biosynthetic process	1	702.2×	0.009	GFI1
sterol homeostasis	1	702.2×	0.009	ABCD1
long-chain fatty acid import into peroxisome	1	561.7×	0.009	ABCD1
regulation of fatty acid beta-oxidation	1	468.1×	0.009	ABCD1
long-chain fatty acid catabolic process	1	468.1×	0.009	ABCD1
myelin maintenance	1	468.1×	0.009	ABCD1
regulation of mitochondrial depolarization	1	468.1×	0.009	ABCD1
tRNA threonylcarbamoyladenosine metabolic process	1	468.1×	0.009	LAGE3
fatty acid elongation	1	401.2×	0.009	ABCD1
very long-chain fatty acid catabolic process	1	401.2×	0.009	ABCD1
pentose-phosphate shunt	1	255.3×	0.012	G6PD
NADP+ metabolic process	1	255.3×	0.012	G6PD
positive regulation of fatty acid beta-oxidation	1	255.3×	0.012	ABCD1
regulation of toll-like receptor signaling pathway	1	255.3×	0.012	GFI1
fatty acid derivative biosynthetic process	1	255.3×	0.012	ABCD1
negative regulation of cell growth involved in cardiac muscle cell development	1	234.1×	0.012	G6PD
glucose 6-phosphate metabolic process	1	216.1×	0.012	G6PD
negative regulation of wound healing	1	216.1×	0.012	CASK
regulation of cellular response to oxidative stress	1	216.1×	0.012	ABCD1
regulation of oxidative phosphorylation	1	200.6×	0.013	ABCD1

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
G6PD	BREXANOLONE
CASK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASK	9	4
G6PD	8	4
LAGE3	0	0
DUSP9	0	0
GFI1	0	0
ABCD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
EBSELEN	3	G6PD
LESTAURTINIB	3	CASK
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD
BMS-387032	1	CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CASK	92	Binding:92
G6PD	49	Binding:46, ADMET:2, Functional:1
GFI1	6	Binding:6
LAGE3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PD	1.1.1.49	glucose-6-phosphate dehydrogenase (NADP+)
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
DUSP9	3.1.3.48	protein-tyrosine-phosphatase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
G6PD	1

Chemical tractability of cohort targets

17 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.

Compound	Max phase	Cohort target (bioactivity)
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
EBSELEN	3	G6PD
LESTAURTINIB	3	CASK
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD
BMS-387032	1	CASK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	G6PD, CASK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	DUSP9, ABCD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LAGE3, GFI1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LAGE3	1	—
DUSP9	0	—
GFI1	6	—
ABCD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.