Sickle cell disease

Summary

Sickle cell disease (MONDO:0011382) is a disease caused by HBB (GenCC Strong), with 6 cohort genes (5 GWAS associations across 4 studies) and 932 clinical trials. Top therapeutic interventions include alemtuzumab, voxelotor, and hydroxyurea.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: HBB (GenCC Strong)
• Cohort genes: 6
• GWAS associations: 5
• ClinVar variants: 123
• Phenotypes (HPO): 37
• Clinical trials: 932

Clinical features

Epidemiology

Prevalence records

12 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Europe	Validated
Annual incidence	1-5 / 10 000	21.6262	Brazil	Validated
Point prevalence	1-5 / 10 000	30	United States	Validated
Prevalence at birth	1-5 / 10 000	42	France	Validated
Prevalence at birth	1-5 / 10 000	25	Germany	Validated
Prevalence at birth	1-5 / 10 000	47.5	Belgium	Validated
Prevalence at birth	1-5 / 10 000	32.8	United States	Validated
Prevalence at birth	1-5 / 10 000	41.7	United Kingdom	Not yet validated
Prevalence at birth	>1 / 1000	344.8	Guadeloupe	Not yet validated
Prevalence at birth	>1 / 1000	248.75	Martinique	Not yet validated
Prevalence at birth	>1 / 1000	467.3	Guyana	Not yet validated
Prevalence at birth	1-5 / 10 000	20.15	Reunion	Not yet validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0004870	Chronic hemolytic anemia	Obligate (100%)
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0012531	Pain	Very frequent (80-99%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001743	Abnormality of the spleen	Frequent (30-79%)
HP:0001891	Iron deficiency anemia	Frequent (30-79%)
HP:0001894	Thrombocytosis	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002754	Osteomyelitis	Frequent (30-79%)
HP:0010885	Avascular necrosis	Frequent (30-79%)
HP:0011981	Pigment gallstones	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001406	Intrahepatic cholestasis	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002140	Ischemic stroke	Occasional (5-29%)
HP:0002597	Abnormality of the vasculature	Occasional (5-29%)
HP:0003259	Elevated circulating creatinine concentration	Occasional (5-29%)
HP:0008282	Unconjugated hyperbilirubinemia	Occasional (5-29%)
HP:0011886	Hyphema	Occasional (5-29%)
HP:0011904	Persistence of hemoglobin F	Occasional (5-29%)
HP:0012418	Hypoxemia	Occasional (5-29%)
HP:0025326	Retinal arterial occlusion	Occasional (5-29%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Occasional (5-29%)
HP:0031090	Finger dactylitis	Occasional (5-29%)
HP:0034336	Splenic infarction	Occasional (5-29%)
HP:0200023	Priapism	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)
HP:0001931	Hypochromic anemia	Very rare (<1-4%)
HP:0001935	Microcytic anemia	Very rare (<1-4%)
HP:0005518	Increased mean corpuscular volume	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	sickle cell disease
Mondo ID	MONDO:0011382
MeSH	D000755
OMIM	603903
Orphanet	232
DOID	DOID:0081445, DOID:10923
ICD-10-CM	D57.2
NCIT	C34383
UMLS	C0002895
MedGen	287
GARD	0008614
MedDRA	10040641
NORD	1714
Is cancer (heuristic)	no

Also known as: Haemoglobin S disease · Haemoglobin S disease without crisis · Hb-S/Hb-C disease · HbS disease · Hemoglobin S disease · HPA 1 recognition polymorphism, beta-globin-related · HPA1 · sickle cell anemia · Sickle Cell Disease · sickle cell disease · sickle-cell/Hb-C disease without crisis · sickling disorder due to Haemoglobin S · sickling disorder due to Hemoglobin S

Data availability: 123 ClinVar variants · 5 GWAS associations (4 studies) · 3 GenCC gene-disease records · 85 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › sickle cell disease

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (2): sickle cell-hemoglobin c disease syndrome, sickle cell disease due to hemoglobin S and a non-S/non-C hemoglobin variant

Genetics & variants

GWAS landscape

5 GWAS associations across 4 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs73404549	3e-61	HBG2, HBE1	?	21.96
rs2445284	1e-29	OR51L1 - OR51P1P	G	0.82
rs7948471	3e-10	HBG2, OR51B5, HBE1, OR51I2	A	0.26
rs7203560	2e-09	NPRL3	C	0.44
rs766432	9e-07	BCL11A	?	0.22

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90481652	Verma A	2024	1,396	120,613	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST000513	Sebastiani P	2009	177	0	Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.
GCST90837517	Koyama S	2025	0	0	Genetics and context for precision health in Greater Boston.
GCST001862	Milton JN	2013	0	0	Genetic determinants of haemolysis in sickle cell anaemia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	4
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs73404549	11	5299424	C>T	0.05	intron_variant	HBG2, HBE1	3e-61	Tier 4: intronic/intergenic
rs2445284	11	5008473	C>A,T	0.05	intergenic_variant	OR51L1 - OR51P1P	1e-29	Tier 4: intronic/intergenic
rs7948471	11	5450516	G>A	0.21	intron_variant	HBG2, OR51B5, HBE1, OR51I2	3e-10	Tier 4: intronic/intergenic
rs7203560	16	134391	T>G	0.07	intron_variant	NPRL3	2e-09	Tier 4: intronic/intergenic
rs766432	2	60492835	C>A,G,T	0.05	intron_variant	BCL11A	9e-07	Tier 4: intronic/intergenic

ClinVar germline variants

123 retrieved; paginated sample, class counts are floors:

43 pathogenic, 24 uncertain significance, 24 pathogenic/likely pathogenic, 23 conflicting classifications of pathogenicity, 5 likely pathogenic, 2 benign/likely benign, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
15126	NM_000518.4(HBB):c.19G>A (p.Glu7Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15152	NM_000518.4(HBB):c.364G>C (p.Glu122Gln)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15161	NM_000518.5(HBB):c.79G>A (p.Glu27Lys)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15234	NM_000518.4(HBB):c.92G>C (p.Arg31Thr)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15239	NM_000518.5(HBB):c.82G>T (p.Ala28Ser)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15292	NM_000518.4(HBB):c.364G>A (p.Glu122Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15300	NM_000518.5(HBB):c.61G>A (p.Val21Met)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15333	NM_000518.5(HBB):c.20A>T (p.Glu7Val)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15352	NM_000518.4(HBB):c.332T>C (p.Leu111Pro)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15401	NM_000518.5(HBB):c.52A>T (p.Lys18Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15402	NM_000518.5(HBB):c.118C>T (p.Gln40Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15404	NM_000518.5(HBB):c.364G>T (p.Glu122Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15407	NM_000518.5(HBB):c.184A>T (p.Lys62Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15408	NM_000518.5(HBB):c.108C>A (p.Tyr36Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15413	NM_000518.5(HBB):c.25_26del (p.Lys9fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15414	NM_000518.5(HBB):c.51del (p.Lys18fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15415	NM_000518.5(HBB):c.135del (p.Phe46fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15417	NM_000518.5(HBB):c.126_129del (p.Phe42fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15418	NM_000518.5(HBB):c.20del (p.Glu7fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15419	NM_000518.5(HBB):c.217dup (p.Ser73fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15422	NM_000518.5(HBB):c.17_18del (p.Pro6fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15426	NM_000518.5(HBB):c.45dup (p.Trp16fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15431	NM_000518.5(HBB):c.112del (p.Trp38fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15432	NM_000518.5(HBB):c.85dup (p.Leu29fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15434	NM_000518.5(HBB):c.2T>G (p.Met1Arg)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15436	NM_000518.5(HBB):c.92+1G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15438	NM_000518.5(HBB):c.315+1G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15446	NM_000518.5(HBB):c.93-1G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15447	NM_000518.5(HBB):c.92+5G>C	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15448	NM_000518.5(HBB):c.92+5G>T	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 33 · Orphanet: 32 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
BCL11A	BCL11A	GWAS, Orphanet

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
HBB	Strong	Autosomal recessive	sickle cell disease	33

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HBB	Orphanet:2132	Hemoglobin C disease
HBB	Orphanet:2133	Hemoglobin E disease
HBB	Orphanet:231214	Beta-thalassemia major
HBB	Orphanet:231222	Beta-thalassemia intermedia
HBB	Orphanet:231226	Unstable beta globin chain variant disease
HBB	Orphanet:231237	Delta-beta-thalassemia
HBB	Orphanet:231242	Hemoglobin C-beta-thalassemia syndrome
HBB	Orphanet:231249	Hemoglobin E-beta-thalassemia syndrome
HBB	Orphanet:232	Sickle cell anemia
HBB	Orphanet:247511	Autosomal dominant secondary polycythemia
HBB	Orphanet:251365	Sickle cell S-C disease
HBB	Orphanet:251370	Sickle cell S-D Punjab disease
HBB	Orphanet:251375	Sickle cell S-E disease
HBB	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
HBB	Orphanet:330041	Hemoglobin M disease
HBB	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
HBB	Orphanet:695140	Sickle cell-beta zero-thalassemia
HBB	Orphanet:695147	Sickle cell-beta plus-thalassemia
HBB	Orphanet:699822	Sickle cell S-Lepore disease
HBB	Orphanet:700090	Sickle cell S-O Arab disease
HBB	Orphanet:700107	Sickle cell S-other specified hemoglobin variant
HBB	Orphanet:700111	Homozygous hemoglobin O Arab disease
HBB	Orphanet:715125	Hemoglobin E-beta-thalassemia intermedia
HBB	Orphanet:715128	Hemoglobin E-beta-thalassemia major
HBB	Orphanet:715135	Hemoglobin Lepore-beta-thalassemia intermedia
HBB	Orphanet:715140	Hemoglobin Lepore-beta-thalassemia major
HBB	Orphanet:715143	Heterozygous beta-thalassemia intermedia with supernumerary alpha-globin gene
HBB	Orphanet:715157	Low oxygen affinity beta chain hemoglobin disease
HBB	Orphanet:90039	Hemoglobin D disease
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
NPRL3	Orphanet:98820	Familial focal epilepsy with variable foci

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	5
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HBB	HGNC:4827	ENSG00000244734	P68871	Hemoglobin subunit beta	gencc,clinvar
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	gwas
NPRL3	HGNC:14124	ENSG00000103148	Q12980	GATOR1 complex protein NPRL3	gwas
OR51L1	HGNC:14759	ENSG00000176798	Q8NGJ5	Olfactory receptor 51L1	gwas
OR51I1	HGNC:15200	ENSG00000167359	Q9H343	Olfactory receptor 51I1	gwas
OR51I2	HGNC:15201	ENSG00000187918	Q9H344	Olfactory receptor 51I2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HBB	Hemoglobin subunit beta	Involved in oxygen transport from the lung to the various peripheral tissues.
BCL11A	BCL11 transcription factor A	Transcription factor.
NPRL3	GATOR1 complex protein NPRL3	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
OR51L1	Olfactory receptor 51L1	Odorant receptor.
OR51I1	Olfactory receptor 51I1	Odorant receptor.
OR51I2	Olfactory receptor 51I2	Odorant receptor.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.5

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
GPCR	3	12.0×	0.004
Transcription factor	1	1.4×	0.809
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
NPRL3	Other/Unknown	no		Npr3, HTH_NPRL3
OR51L1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
OR51I1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
OR51I2	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM

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)	3
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
trabecular bone tissue	1
vena cava	1
cortical plate	1
ganglionic eminence	1
primary visual cortex	1
blood	1
hindlimb stylopod muscle	1
right uterine tube	1
colonic epithelium	1
sural nerve	1
ventricular zone	1
nasal cavity epithelium	1
oocyte	1
skeletal muscle tissue of rectus abdominis	1
ileal mucosa	1
pancreatic ductal cell	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HBB	284	broad	marker	monocyte, trabecular bone tissue, vena cava
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
NPRL3	276	ubiquitous	marker	blood, hindlimb stylopod muscle, right uterine tube
OR51L1	2		marker	colonic epithelium, sural nerve, ventricular zone
OR51I1	3		yes	skeletal muscle tissue of rectus abdominis, nasal cavity epithelium, oocyte
OR51I2	4		marker	tibialis anterior, ileal mucosa, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCL11A	2,389
NPRL3	1,511
HBB	454
OR51I1	230
OR51I2	202
OR51L1	193

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBB	P68871	350
BCL11A	Q9H165	17
NPRL3	Q12980	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR51I2	Q9H344	90.87
OR51L1	Q8NGJ5	89.38
OR51I1	Q9H343	88.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
Heme assimilation	1	634.4×	0.016	HBB
Expression and translocation of olfactory receptors	3	14.1×	0.016	OR51L1, OR51I1, OR51I2
Erythrocytes take up oxygen and release carbon dioxide	1	211.5×	0.023	HBB
ALK mutants bind TKIs	1	158.6×	0.023	BCL11A
Erythrocytes take up carbon dioxide and release oxygen	1	146.4×	0.023	HBB
Scavenging of heme from plasma	1	146.4×	0.023	HBB
Formation of the embryonic stem cell BAF (esBAF) complex	1	100.2×	0.028	BCL11A
Chaperone Mediated Autophagy	1	82.8×	0.029	HBB
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	76.1×	0.029	BCL11A
Late endosomal microautophagy	1	54.4×	0.037	HBB
Signaling by ALK in cancer	1	45.3×	0.040	BCL11A
Heme signaling	1	35.9×	0.046	HBB
Amino acids regulate mTORC1	1	33.4×	0.046	NPRL3
Cytoprotection by HMOX1	1	30.7×	0.046	HBB
Signaling by ALK fusions and activated point mutants	1	25.0×	0.051	BCL11A
Olfactory Signaling Pathway	1	24.1×	0.051	OR51L1
Factors involved in megakaryocyte development and platelet production	1	11.1×	0.102	HBB
Diseases of signal transduction by growth factor receptors and second messengers	1	9.5×	0.112	BCL11A
Neutrophil degranulation	1	3.9×	0.246	HBB
Disease	1	2.2×	0.380	BCL11A

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
cellular response to lipid	3	247.8×	6e-06	OR51L1, OR51I1, OR51I2
negative regulation of neuron remodeling	1	2808.7×	0.005	BCL11A
negative regulation of branching morphogenesis of a nerve	1	2808.7×	0.005	BCL11A
sensory perception of smell	2	52.0×	0.006	OR51I1, OR51I2
negative regulation of protein homooligomerization	1	936.2×	0.008	BCL11A
negative regulation of dendrite extension	1	702.2×	0.009	BCL11A
nitric oxide transport	1	561.7×	0.010	HBB
negative regulation of dendrite development	1	351.1×	0.012	BCL11A
positive regulation of collateral sprouting	1	312.1×	0.012	BCL11A
cellular oxidant detoxification	1	312.1×	0.012	HBB
renal absorption	1	280.9×	0.012	HBB
cellular response to L-glutamate	1	280.9×	0.012	BCL11A
negative regulation of collateral sprouting	1	255.3×	0.012	BCL11A
carbon dioxide transport	1	216.1×	0.013	HBB
oxygen transport	1	175.5×	0.015	HBB
regulation of dendrite development	1	165.2×	0.015	BCL11A
aorta morphogenesis	1	147.8×	0.015	NPRL3
cardiac muscle tissue development	1	147.8×	0.015	NPRL3
negative regulation of axon extension	1	122.1×	0.017	BCL11A
hydrogen peroxide catabolic process	1	112.3×	0.017	HBB
blood vessel diameter maintenance	1	104.0×	0.018	HBB
erythrocyte development	1	87.8×	0.020	HBB
ventricular septum development	1	82.6×	0.020	NPRL3
response to hydrogen peroxide	1	78.0×	0.020	HBB
positive regulation of nitric oxide biosynthetic process	1	75.9×	0.020	HBB
platelet aggregation	1	56.2×	0.025	HBB
protein sumoylation	1	54.0×	0.025	BCL11A
negative regulation of TORC1 signaling	1	54.0×	0.025	NPRL3
cellular response to amino acid starvation	1	53.0×	0.025	NPRL3
roof of mouth development	1	41.3×	0.031	NPRL3

Therapeutics

Drugs indicated for this disease

7 approved, 23 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Crizanlizumab	Approved (phase 4)
Deferiprone	Approved (phase 4)
Exagamglogene Autotemcel	Approved (phase 4)
Glutamine	Approved (phase 4)
Hydroxyurea	Approved (phase 4)
Lovotibeglogene Autotemcel	Approved (phase 4)
Voxelotor	Approved (phase 4)
Acetylcysteine	Phase 3 (in late-stage trials)
Alemtuzumab	Phase 3 (in late-stage trials)
Apixaban	Phase 3 (in late-stage trials)
Arginine	Phase 3 (in late-stage trials)
Arginine Hydrochloride	Phase 3 (in late-stage trials)
Deferasirox	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Fludarabine	Phase 3 (in late-stage trials)
Hydromorphone	Phase 3 (in late-stage trials)
Ketamine	Phase 3 (in late-stage trials)
Magnesium Sulfate Anhydrous	Phase 3 (in late-stage trials)
Melphalan	Phase 3 (in late-stage trials)
Methylphenidate	Phase 3 (in late-stage trials)
Morphine	Phase 3 (in late-stage trials)
Oxygen	Phase 3 (in late-stage trials)
Poloxamer	Phase 3 (in late-stage trials)
Prasugrel	Phase 3 (in late-stage trials)
Rivipansel	Phase 3 (in late-stage trials)
Senicapoc	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Ticagrelor	Phase 3 (in late-stage trials)
Vepoloxamer	Phase 3 (in late-stage trials)
Zinc Ion	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcholine, Atorvastatin, Azathioprine, Buprenorphine, Busulfan, Canakinumab, Cannabinol, Chloroquine, Crovalimab, Dalteparin Sodium, Daratumumab, Decitabine, Deferoxamine, Defibrotide, Dipyridamole, Doconexent, Dronabinol, Ergocalciferol, Famotidine, Filgrastim, Fludarabine Phosphate, Folic Acid, Gabapentin, Levetiracetam, Losartan, Magnesium, Methotrexate, Mitapivat, Mometasone, Mometasone Furoate, Montelukast, Mycophenolate Mofetil, Niacin, Nitric Oxide, Nitrous Oxide, OMEGA-3 FATTY ACIDS, Pectin, Phenytoin, Plerixafor, Propranolol, Regadenoson Anhydrous, Rifaximin, Riociguat, Rituximab, Rivaroxaban, Simvastatin, Sirolimus, Tacrolimus Anhydrous, Thiotepa, Tilarginine, Vorinostat, Zinc Sulfate.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 2 of 6 evidence-associated genes (33%) 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
HBB	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HBB	23	4
BCL11A	0	0
NPRL3	0	0
OR51L1	0	0
OR51I1	0	0
OR51I2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HBB	68	Binding:50, Functional:18

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

23 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)
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HBB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	3	OR51L1, OR51I1, OR51I2
E	Difficult family or no structure, no drug	2	BCL11A, NPRL3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BCL11A	0	—
NPRL3	0	—
OR51L1	0	—
OR51I1	0	—
OR51I2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 932.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	486
PHASE2	165
PHASE1	85
PHASE3	73
PHASE1/PHASE2	65
PHASE4	30
PHASE2/PHASE3	14
EARLY_PHASE1	14

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04657822	PHASE4	RECRUITING	Rollover Study for Patients With Sickle Cell Disease Who Have Completed a Prior Novartis-Sponsored Crizanlizumab Study
NCT05730205	PHASE4	RECRUITING	Effects of the Contraceptive Implant in Women With Sickle Cell Disease
NCT06526117	PHASE4	RECRUITING	Stroke Prevention in Nigeria 2 Trial
NCT06579703	PHASE4	NOT_YET_RECRUITING	Ketorolac for Acute Vaso-Occlusive Crisis in Pediatric Sickle Cell Disease
NCT06665997	PHASE4	RECRUITING	Clinical and Biomarker Effects of Depot Medroxyprogesterone Acetate in Females With Sickle Cell Disease
NCT06979492	PHASE4	RECRUITING	Prophylactic Transfusion In Pregnant in Women With Sickle Cell Disease
NCT07177300	PHASE4	RECRUITING	Effectiveness of Nontraditional Hydroxyurea Algorithms: Novel and Clinical Evaluations (ENHANCE)
NCT07488520	PHASE4	NOT_YET_RECRUITING	Integrating Point of Care Testing (POCT) For Newborn Screening and Early Care for Sickle Cell Disease in Yopougon, Côte d’Ivoire
NCT00252122	PHASE4	TERMINATED	Pilot Study on the Effects of Intravenous Ketamine on Acute Pain Crisis in Patients With Sickle Cell Disease
NCT00513864	PHASE4	WITHDRAWN	Assessment of Opioid Analgesia in Sickle Cell
NCT00749515	PHASE4	COMPLETED	Pilot Study for Patients With Poor Response to Deferasirox
NCT00880373	PHASE4	TERMINATED	Ibuprofen and Opioid (Morphine or Diamorphine) for Acute Pain in Sickle Cell Disease - Sickle With Ibuprofen & Morphine
NCT00937144	PHASE4	WITHDRAWN	Endothelial Function in Patients With Sickle Cell Anemia Before and After Sildenafil
NCT02041299	PHASE4	TERMINATED	Efficacy and Safety of Ferriprox® in Patients With Sickle Cell Disease or Other Anemias
NCT02149537	PHASE4	COMPLETED	Risk Clinical Stratification of Sickle Cell Disease in Nigeria, Assessment of Efficacy/Safety of Hydroxyurea Treatment
NCT02222246	PHASE4	COMPLETED	Comparing Acute Pain Management Protocols for Patients With Sickle Cell Disease
NCT02443545	PHASE4	TERMINATED	Long-term Safety and Efficacy of Ferriprox® in Iron Overloaded Patients With Sickle Cell Disease or Other Anemias
NCT02522104	PHASE4	COMPLETED	Evaluation of the Impact of Renal Function on the Pharmacokinetics of SIKLOS ® (DARH)
NCT02594462	PHASE4	COMPLETED	Contraception in Women With Sickle Cell Disease
NCT02731157	PHASE4	COMPLETED	Rejuvesol® Washed RBC in Sickle Cell Patients Requiring Frequent Transfusions
NCT03682211	PHASE4	COMPLETED	Intranasal Fentanyl Versus Intravenous Morphine in the Treatment of Severe Painful Sickle Cell Crises in Children
NCT03903133	PHASE4	COMPLETED	Endothelial Monocyte-activating Polypeptide-II in Egyptian Sickle Patients
NCT04400487	PHASE4	COMPLETED	Actigraphy Improvement With Voxelotor (ActIVe) Study
NCT04581356	PHASE4	COMPLETED	Voxelotor Sickle Cell Exercise Study
NCT04662931	PHASE4	COMPLETED	An Indian Multi-centric Phase IV Study to Assess the Safety of Crizanlizumab in Sickle Cell Disease Patients
NCT04684381	PHASE4	COMPLETED	Pharmacokinetics and Safety of Endari (L-glutamine) in Sickle Cell Disease Patients
NCT05081349	PHASE4	COMPLETED	Hydoxycarbamide and L-Carnitine Therapy in Sickle Cell Anemia
NCT05228821	PHASE4	WITHDRAWN	Voxelotor Brain Oxygenation and Neurocognitive Study
NCT05371184	PHASE4	COMPLETED	Glutamine Role in Preventing Vaso-occlusive Crisis Among SCD Patients
NCT05848531	PHASE4	UNKNOWN	Clonidine With Morphine in Patient Controlled Analgesia Pump in Vaso-Occlusive Crisis in Sickle Cell Disease Patient
NCT03814746	PHASE3	ACTIVE_NOT_RECRUITING	Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients
NCT04084080	PHASE3	ACTIVE_NOT_RECRUITING	Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
NCT04208529	PHASE3	ENROLLING_BY_INVITATION	A Long-term Follow-up Study in Participants Who Received CTX001
NCT04293185	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease
NCT04624659	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS)
NCT05031780	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)
NCT05285917	PHASE3	RECRUITING	Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa
NCT05329649	PHASE3	ACTIVE_NOT_RECRUITING	Evaluation of Safety and Efficacy of CTX001 in Pediatric Participants With Severe Sickle Cell Disease (SCD)
NCT05392894	PHASE3	RECRUITING	RElated Haplo-DonoR Haematopoietic stEm Cell Transplantation for Adults With Severe Sickle Cell Disease
NCT05431088	PHASE2/PHASE3	RECRUITING	A Phase 2/3 Study in Adult and Adolescent Participants With SCD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALEMTUZUMAB	4	22
VOXELOTOR	4	19
HYDROXYUREA	4	17
CRIZANLIZUMAB	4	12
PLERIXAFOR	4	11
KETAMINE	4	7
DEFERASIROX	4	6
GLUTAMINE	4	6
MORPHINE	4	6
DEFEROXAMINE	4	5
EXAGAMGLOGENE AUTOTEMCEL	4	4
MITAPIVAT	4	4
NITRIC OXIDE	4	4
NITROUS ACID	4	4
ACETYLCHOLINE	4	3
DEFERIPRONE	4	3
DEXTROMETHORPHAN	4	3
PENTOSTATIN	4	3
REGADENOSON	4	3
ZINC SULFATE	4	3
CLOTRIMAZOLE	4	2
CODEINE	4	2
CROVALIMAB	4	2
DRONABINOL	4	2
FLUDARABINE PHOSPHATE	4	2
2-MERCAPTOETHANESULFONIC ACID	4	1
ABCIXIMAB	4	1
ACETYLCYSTEINE	4	1
ALEFACEPT	4	1
AMBRISENTAN	4	1