Cystic fibrosis

Summary

Cystic fibrosis (MONDO:0009061) is a disease caused by CFTR (GenCC Definitive), with 43 cohort genes (37 GWAS associations across 4 studies) and 1,429 clinical trials. Top therapeutic interventions include ivacaftor, tobramycin, and tezacaftor.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: CFTR (GenCC Definitive)
• Cohort genes: 43
• GWAS associations: 37
• ClinVar variants: 5,499
• Phenotypes (HPO): 35
• Clinical trials: 1,429

Clinical features

Epidemiology

Prevalence records

57 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	11.1319	Europe	Validated
Prevalence at birth	1-5 / 10 000	19.3912	Europe	Validated
Annual incidence	1-5 / 10 000	13.1995	Brazil	Validated
Point prevalence	1-9 / 100 000	8.39	Austria	Validated
Point prevalence	1-5 / 10 000	20.1429	Belgium	Validated
Point prevalence	1-9 / 100 000	2.26	Bulgaria	Validated
Point prevalence	1-9 / 100 000	3.35	Cyprus	Validated
Point prevalence	1-9 / 100 000	8.7775	Czech Republic	Validated
Point prevalence	1-9 / 100 000	9.9946	Denmark	Validated
Point prevalence	1-9 / 100 000	6.18	Estonia	Validated
Point prevalence	1-9 / 100 000	1.1027	Finland	Validated
Point prevalence	1-5 / 10 000	12.1416	France	Validated
Point prevalence	1-5 / 10 000	11.1954	Germany	Validated
Point prevalence	1-9 / 100 000	5.21	Greece	Validated
Point prevalence	1-9 / 100 000	4.09	Hungary	Validated
Point prevalence	1-5 / 10 000	20.8733	Ireland	Validated
Point prevalence	1-5 / 10 000	10.2236	Italy	Validated
Point prevalence	1-9 / 100 000	1.04	Latvia	Validated
Point prevalence	1-9 / 100 000	1.3	Lithuania	Validated
Point prevalence	1-9 / 100 000	4.31	Luxembourg	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0001738	Exocrine pancreatic insufficiency	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002110	Bronchiectasis	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0006536	Airway obstruction	Very frequent (80-99%)
HP:0012236	Elevated sweat chloride	Very frequent (80-99%)
HP:0012873	Absent vas deferens	Very frequent (80-99%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0003251	Male infertility	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001392	Abnormality of the liver	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002035	Rectal prolapse	Occasional (5-29%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0002570	Steatorrhea	Occasional (5-29%)
HP:0002724	Recurrent Aspergillus infections	Occasional (5-29%)
HP:0002726	Recurrent Staphylococcus aureus infections	Occasional (5-29%)
HP:0002783	Recurrent lower respiratory tract infections	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0004401	Meconium ileus	Occasional (5-29%)
HP:0005376	Recurrent Haemophilus influenzae infections	Occasional (5-29%)
HP:0032342	Reduced forced expiratory volume in one second	Occasional (5-29%)
HP:0045082	Decreased body mass index	Occasional (5-29%)
HP:0000246	Sinusitis	Occasional (5-29%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000787	Nephrolithiasis	Very rare (<1-4%)
HP:0000939	Osteoporosis	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0002105	Hemoptysis	Very rare (<1-4%)
HP:0002107	Pneumothorax	Very rare (<1-4%)
HP:0002842	Recurrent Burkholderia cepacia infections	Very rare (<1-4%)
HP:0032261	Nontuberculous mycobacterial pulmonary infection	Very rare (<1-4%)
HP:0100582	Nasal polyposis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cystic fibrosis
Mondo ID	MONDO:0009061
MeSH	D003550
OMIM	219700
Orphanet	586
DOID	DOID:1485
ICD-10-CM	E84
ICD-11	514403112
NCIT	C2975
SNOMED CT	190905008
UMLS	C0010674
MedGen	41393
GARD	0006233
MedDRA	10011762
NORD	1026
Is cancer (heuristic)	no

Also known as: CF · cystic fibrosis · cystic fibrosis lung disease, modifier of · fibrocystic disease of the pancreas · mucoviscidosis · pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis

Data availability: 5,499 ClinVar variants · 37 GWAS associations (4 studies) · 23 GenCC gene-disease records · 288 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › cystic fibrosis

Related subtypes (58): lower respiratory tract disorder, respiratory system cancer, respiratory system benign neoplasm, allergic respiratory disease, paranasal sinus disorder, upper respiratory tract disorder, pertussis, severe acute respiratory syndrome, sleep apnea syndrome, diaphragm disorder, pulmonary tuberculosis, altitude sickness, perinatal asphyxia, pulmonary nodular lymphoid hyperplasia, tracheobronchopathia osteochondroplastica, Williams-Campbell syndrome, growth delay-hydrocephaly-lung hypoplasia syndrome, laryngo-onycho-cutaneous syndrome, congenital pulmonary lymphangiectasia, familial primary pulmonary hypoplasia, Mounier-Kuhn syndrome, Young syndrome, lung agenesis-heart defect-thumb anomalies syndrome, sudden infant death-dysgenesis of the testes syndrome, alpha 1-antitrypsin deficiency, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, autoimmune interstitial lung disease-arthritis syndrome, mucopolysaccharidosis-plus syndrome, congenital bronchobiliary fistula, bronchogenic cyst, primary ciliary dyskinesia, congenital pulmonary airway malformation, transient hyperammonemia of the newborn, congenital pulmonary sequestration, Siegler-Brewer-Carey syndrome, tracheal agenesis, 16q24.1 microdeletion syndrome, staphylococcal necrotizing pneumonia, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, plastic bronchitis, recurrent respiratory papillomatosis, IgG4-related mediastinitis, bronchopulmonary dysplasia, infantile apnea, diffuse alveolar hemorrhage, respiratory or thoracic malformation, pulmonary agenesis, eosinophilic granuloma, disorder of pharynx, respiratory tract neoplasm, pulmonary alveolar proteinosis with hypogammaglobulinemia, respiratory tract infectious disorder, Middle East respiratory syndrome, reactive airway disease, acinar dysplasia, pulmonary hypoplasia, isolated left bronchial isomerism, bronchiectasis and nasal polyposis

Subtypes (1): cystic fibrosis-gastritis-megaloblastic anemia syndrome

Genetics & variants

GWAS landscape

37 GWAS associations across 4 studies. Top hits map to 9 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs113993960	4e-95	CFTR	?	14.87
rs57221529	7e-12	CEP72-DT	G	0.16
rs3103933	3e-11	MUC4	A	0.12
rs7929679	2e-10	EHF - APIP	G	0.11
rs7879546	5e-10	AGTR2 - RNU6-154P	C
rs56302516	8e-10	SLC9A3	T
rs12793173	1e-09	EHF - APIP	C
rs4077468	1e-09	SLC26A9 - RAB7B	A	1.39
rs117230773	2e-09	HLA-DRB9	A	0.13
rs546131	3e-09	EHF - APIP	G	0.09
rs5952223	3e-08	AGTR2 - RNU6-154P	T	0.08
rs2688482	7e-08	MUC4	T	0.12
rs9268905	1e-07	HLA-DRB9	C
rs1403543	2e-06	AGTR2	A
rs7112043	3e-06	EHF - APIP	T
rs12188164	4e-06	PDCD6-AHRR, AHRR	A
rs11645366	7e-06	RNU6-21P - DPPA3P11	C
rs12883884	8e-06	SLC8A3	T

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST001077	Wright FA	2011	2,317	0	Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.
GCST002025	Blackman SM	2013	644	2,415	Genetic modifiers of cystic fibrosis-related diabetes.
GCST000346	Gu Y	2009	160	0	Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease.
GCST90837488	Koyama S	2025	0	0	Genetics and context for precision health in Greater Boston.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	17

MAF distribution

Bucket	Variants
common (>=0.05)	18
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	13
intergenic_variant	4
inframe_insertion	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs113993960	7	117559591	ATCT>A,ATCTTCT	0.05	inframe_insertion	CFTR	4e-95	Tier 1: coding
rs57221529	5	586509	A>G,T	0.19	intron_variant	CEP72-DT	7e-12	Tier 4: intronic/intergenic
rs3103933	3	195758569	A>C,G,T	0.37	intron_variant	MUC4	3e-11	Tier 4: intronic/intergenic
rs7929679	11	34784302	A>G	0.5	intron_variant	EHF - APIP	2e-10	Tier 4: intronic/intergenic
rs7879546	X	116217020	T>C	0.48	intergenic_variant	AGTR2 - RNU6-154P	5e-10	Tier 4: intronic/intergenic
rs56302516	5	518319	C>G,T	0.24	intron_variant	SLC9A3	8e-10	Tier 4: intronic/intergenic
rs12793173	11	34812657	T>C	0.24	intron_variant	EHF - APIP	1e-09	Tier 4: intronic/intergenic
rs4077468	1	205945629	A>G	0.42	intergenic_variant	SLC26A9 - RAB7B	1e-09	Tier 4: intronic/intergenic
rs117230773	6	32465964		0.36	intron_variant	HLA-DRB9	2e-09	Tier 4: intronic/intergenic
rs546131	11	34830213	G>C	0.36	intron_variant	EHF - APIP	3e-09	Tier 4: intronic/intergenic
rs5952223	X	116255308	C>T	0.28	intergenic_variant	AGTR2 - RNU6-154P	3e-08	Tier 4: intronic/intergenic
rs2688482	3	195802247	T>A,C	0.31	intron_variant	MUC4	7e-08	Tier 4: intronic/intergenic
rs9268905	6	32464300	G>A,C,T	0.32	intron_variant	HLA-DRB9	1e-07	Tier 4: intronic/intergenic
rs1403543	X	116170939	G>A,T	0.49	intron_variant	AGTR2	2e-06	Tier 4: intronic/intergenic
rs7112043	11	34767839	A>T	0.41	intron_variant	EHF - APIP	3e-06	Tier 4: intronic/intergenic
rs12188164	5	428121	C>A	0.38	intron_variant	PDCD6-AHRR, AHRR	4e-06	Tier 4: intronic/intergenic
rs11645366	16	62343249	C>T	0.23	intergenic_variant	RNU6-21P - DPPA3P11	7e-06	Tier 4: intronic/intergenic
rs12883884	14	70050466	T>A,C,G	0.39	intron_variant	SLC8A3	8e-06	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

333 likely benign, 147 uncertain significance, 49 pathogenic, 20 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 16 likely pathogenic, 12 benign, 5 benign/likely benign, 1 conflicting classifications of pathogenicity; other, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300167	NM_000492.4(CFTR):c.[1523T>G;3752G>A]		Pathogenic	reviewed by expert panel
1300168	NM_000492.4(CFTR):c.[3846G>A;3848G>T]		Pathogenic	reviewed by expert panel
1320029	NM_000492.4(CFTR):c.[4C>T;7A>T]		Pathogenic	reviewed by expert panel
1027585	NM_000492.4(CFTR):c.1585-2A>T	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048778	NM_000492.4(CFTR):c.89dup (p.Arg31fs)	CFTR	Pathogenic	criteria provided, single submitter
1065566	NM_000492.4(CFTR):c.327T>G (p.Tyr109Ter)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069281	NM_000492.4(CFTR):c.2560dup (p.Thr854fs)	CFTR	Pathogenic	criteria provided, single submitter
1069526	NM_000492.4(CFTR):c.489+1G>A	CFTR	Pathogenic	criteria provided, multiple submitters, no conflicts
1069549	NM_000492.4(CFTR):c.300_301del (p.Leu101fs)	CFTR	Pathogenic	criteria provided, single submitter
1070381	NC_000007.13:g.(?117304664)(117306195_?)del	CFTR	Pathogenic	criteria provided, single submitter
1070382	NC_000007.13:g.(?117174320)(117176752_?)del	CFTR	Pathogenic	criteria provided, single submitter
1070544	NM_000492.4(CFTR):c.4340del (p.Val1447fs)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073653	NM_000492.4(CFTR):c.1573del (p.Gln525fs)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074249	NC_000007.13:g.(?117218381)(117254777_?)del	CFTR	Pathogenic	criteria provided, single submitter
1074251	NC_000007.13:g.(?117246713)(117251872_?)del	CFTR	Pathogenic	criteria provided, single submitter
1177286	NM_000492.4(CFTR):c.1132C>T (p.Gln378Ter)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185022	NM_000492.4(CFTR):c.2335C>T (p.Gln779Ter)	CFTR	Pathogenic	criteria provided, single submitter
1275739	NM_000492.4(CFTR):c.2620-674_3367+232del	CFTR	Pathogenic	criteria provided, single submitter
1300161	NM_000492.3:c.54-5842_489+401del	CFTR	Pathogenic	reviewed by expert panel
1300162	NM_000492.3:c.(273+1_274-1)_(1584+1_1585-1)del	CFTR	Pathogenic	reviewed by expert panel
1300163	NM_000492.4(CFTR):c.761del (p.Lys254fs)	CFTR	Pathogenic	reviewed by expert panel
1300164	NM_000492.4(CFTR):c.580G>A (p.Gly194Arg)	CFTR	Pathogenic	reviewed by expert panel
1300165	NM_000492.4(CFTR):c.3382A>T (p.Arg1128Ter)	CFTR	Pathogenic	reviewed by expert panel
1300166	NM_000492.4(CFTR):c.3600del (p.Asp1201fs)	CFTR	Pathogenic	reviewed by expert panel
1328993	NM_000492.4(CFTR):c.396del (p.Ile132fs)	CFTR	Pathogenic	criteria provided, single submitter
1330378	NM_000492.4(CFTR):c.3741_3745dup (p.Gly1249fs)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330401	NM_000492.4(CFTR):c.580G>T (p.Gly194Ter)	CFTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331481	NC_000007.13:g.(117120202_117144306)_(117149197_117170952)del	CFTR	Pathogenic	criteria provided, single submitter
1332860	NM_000492.4(CFTR):c.2848del (p.His950fs)	CFTR	Pathogenic	criteria provided, single submitter
1353073	NM_000492.4(CFTR):c.307G>T (p.Gly103Ter)	CFTR	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 75 · Orphanet: 77 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

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

Gene	HGNC	Evidence routes
SLC6A14	SLC6A14	GWAS, GenCC, Orphanet
SLC9A3	SLC9A3	GWAS, GenCC, Orphanet
SLC26A9	SLC26A9	GWAS, GenCC, 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
CFTR	Definitive	Autosomal recessive	cystic fibrosis	7
CEACAM3	Supportive	Autosomal recessive	cystic fibrosis
CEACAM6	Supportive	Autosomal recessive	cystic fibrosis
CLCA4	Supportive	Autosomal recessive	cystic fibrosis
DCTN4	Supportive	Autosomal recessive	cystic fibrosis
EDNRA	Supportive	Autosomal recessive	cystic fibrosis	6
GCLC	Supportive	Autosomal recessive	cystic fibrosis	5
GSTM3	Supportive	Autosomal recessive	cystic fibrosis
HFE	Supportive	Autosomal recessive	cystic fibrosis	7
HMOX1	Supportive	Autosomal recessive	cystic fibrosis	6
KCNN4	Supportive	Autosomal recessive	cystic fibrosis	5
MIF	Supportive	Autosomal recessive	cystic fibrosis	2
SERPINA1	Supportive	Autosomal recessive	cystic fibrosis	7
SLC11A1	Supportive	Autosomal recessive	cystic fibrosis	2
SLC26A9	Supportive	Autosomal recessive	cystic fibrosis
SLC6A14	Supportive	Autosomal recessive	cystic fibrosis
SLC9A3	Supportive	Autosomal recessive	cystic fibrosis	5
STX1A	Supportive	Autosomal recessive	cystic fibrosis	5
TGFB1	Supportive	Autosomal recessive	cystic fibrosis	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC11A1	Orphanet:3389	Tuberculosis
SLC11A1	Orphanet:586	Cystic fibrosis
SLC6A14	Orphanet:586	Cystic fibrosis
SLC9A3	Orphanet:103908	Congenital sodium diarrhea
SLC9A3	Orphanet:586	Cystic fibrosis
TGFB1	Orphanet:1328	Camurati-Engelmann disease
TGFB1	Orphanet:565788	Infantile inflammatory bowel disease with neurological involvement
TGFB1	Orphanet:586	Cystic fibrosis
SLC26A9	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CFTR	Orphanet:48	Congenital bilateral absence of vas deferens
CFTR	Orphanet:498359	Aquagenic palmoplantar keratoderma
CFTR	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:60033	Idiopathic bronchiectasis
CFTR	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis
HFE	Orphanet:443057	Sporadic porphyria cutanea tarda
HFE	Orphanet:443062	Familial porphyria cutanea tarda
HFE	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HFE	Orphanet:586	Cystic fibrosis
HFE	Orphanet:648581	Digenic hemochromatosis
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin deficiency
STX1A	Orphanet:586	Cystic fibrosis
STX1A	Orphanet:904	Williams syndrome
DCTN4	Orphanet:586	Cystic fibrosis
CEACAM3	Orphanet:586	Cystic fibrosis
CEACAM6	Orphanet:586	Cystic fibrosis
CLCA4	Orphanet:586	Cystic fibrosis
EDNRA	Orphanet:443995	Mandibulofacial dysostosis with alopecia
EDNRA	Orphanet:586	Cystic fibrosis
GCLC	Orphanet:33574	Glutamate-cysteine ligase deficiency
GCLC	Orphanet:586	Cystic fibrosis
GSTM3	Orphanet:586	Cystic fibrosis
HMOX1	Orphanet:562509	Heme oxygenase-1 deficiency
HMOX1	Orphanet:586	Cystic fibrosis
KCNN4	Orphanet:3202	Dehydrated hereditary stomatocytosis
KCNN4	Orphanet:586	Cystic fibrosis
MIF	Orphanet:586	Cystic fibrosis
MIF	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure

Cohort genes → proteins

43 cohort genes, 41 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	10
gwas_and_gencc	3
multi_evidence	30

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC11A1	HGNC:10907	ENSG00000018280	P49279	Natural resistance-associated macrophage protein 1	gencc,clinvar
SLC6A14	HGNC:11047	ENSG00000268104	Q9UN76	Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+)	gwas,gencc
SLC9A3	HGNC:11073	ENSG00000066230	P48764	Sodium/hydrogen exchanger 3	gwas,gencc
TGFB1	HGNC:11766	ENSG00000105329	P01137	Transforming growth factor beta-1 proprotein	gencc,clinvar
SLC26A9	HGNC:14469	ENSG00000174502	Q7LBE3	Solute carrier family 26 member 9	gwas,gencc
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	gencc,clinvar
HFE	HGNC:4886	ENSG00000010704	Q30201	Hereditary hemochromatosis protein	gencc,clinvar
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	gencc,clinvar
STX1A	HGNC:11433	ENSG00000106089	Q16623	Syntaxin-1A	gencc
DCTN4	HGNC:15518	ENSG00000132912	Q9UJW0	Dynactin subunit 4	gencc
CEACAM3	HGNC:1815	ENSG00000170956	P40198	Cell adhesion molecule CEACAM3	gencc
CEACAM6	HGNC:1818	ENSG00000086548	P40199	Cell adhesion molecule CEACAM6	gencc
CLCA4	HGNC:2018	ENSG00000016602	Q14CN2	Calcium-activated chloride channel regulator 4	gencc
EDNRA	HGNC:3179	ENSG00000151617	P25101	Endothelin-1 receptor	gencc
GCLC	HGNC:4311	ENSG00000001084	P48506	Glutamate–cysteine ligase catalytic subunit	gencc
GSTM3	HGNC:4635	ENSG00000134202	P21266	Glutathione S-transferase Mu 3	gencc
HMOX1	HGNC:5013	ENSG00000100292	P09601	Heme oxygenase 1	gencc
KCNN4	HGNC:6293	ENSG00000104783	O15554	Intermediate conductance calcium-activated potassium channel protein 4	gencc
MIF	HGNC:7097	ENSG00000240972	P14174	Macrophage migration inhibitory factor	gencc
SLC8A3	HGNC:11070	ENSG00000100678	P57103	Sodium/calcium exchanger 3	gwas
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
C1QB	HGNC:1242	ENSG00000173369	P02746	Complement C1q subcomponent subunit B	clinvar
ASZ1	HGNC:1350	ENSG00000154438	Q8WWH4	Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
APIP	HGNC:17581	ENSG00000149089	Q96GX9	Methylthioribulose-1-phosphate dehydratase	gwas
CDH8	HGNC:1767	ENSG00000150394	P55286	Cadherin-8	gwas
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	clinvar
MUC20	HGNC:23282	ENSG00000176945	Q8N307	Mucin-20	gwas
CEP72	HGNC:25547	ENSG00000112877	Q9P209	Centrosomal protein of 72 kDa	gwas
EHF	HGNC:3246	ENSG00000135373	Q9NZC4	ETS homologous factor	gwas
AGTR2	HGNC:338	ENSG00000180772	P50052	Type-2 angiotensin II receptor	gwas
EPHX1	HGNC:3401	ENSG00000143819	P07099	Epoxide hydrolase 1	clinvar
AHRR	HGNC:346	ENSG00000063438	A9YTQ3	Aryl hydrocarbon receptor repressor	gwas
FCGR2A	HGNC:3616	ENSG00000143226	P12318	Low affinity immunoglobulin gamma Fc region receptor II-a	clinvar
CFTR-AS1	HGNC:40144	ENSG00000232661		CFTR antisense RNA 1	clinvar
CFTR-AS2	HGNC:40145	ENSG00000083622		CFTR antisense RNA 2	clinvar
HLA-DRA	HGNC:4947	ENSG00000204287	P01903	HLA class II histocompatibility antigen, DR alpha chain	gwas
MBL2	HGNC:6922	ENSG00000165471	P11226	Mannose-binding protein C	clinvar
MUC4	HGNC:7514	ENSG00000145113	Q99102	Mucin-4	gwas
PIK3CG	HGNC:8978	ENSG00000105851	P48736	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	clinvar
PLG	HGNC:9071	ENSG00000122194	P00747	Plasminogen	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC11A1	Natural resistance-associated macrophage protein 1	Macrophage-specific antiporter that fluxes metal ions in either direction against a proton gradient.
SLC6A14	Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+)	Amino acid transporter that plays an important role in the absorption of amino acids in the intestinal tract.
SLC9A3	Sodium/hydrogen exchanger 3	Plasma membrane Na(+)/H(+) antiporter.
TGFB1	Transforming growth factor beta-1 proprotein	Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.
SLC26A9	Solute carrier family 26 member 9	Ion transporter that can act both as an ion channel and anion exchanger.
CFTR	Cystic fibrosis transmembrane conductance regulator	Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.
HFE	Hereditary hemochromatosis protein	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.
STX1A	Syntaxin-1A	Plays an essential role in hormone and neurotransmitter calcium-dependent exocytosis and endocytosis.
DCTN4	Dynactin subunit 4	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
CEACAM3	Cell adhesion molecule CEACAM3	Major granulocyte receptor mediating recognition and efficient opsonin-independent phagocytosis of CEACAM-binding microorganisms, including Neissiria, Moxarella and Haemophilus species, thus playing an important role in the clearance of pa…
CEACAM6	Cell adhesion molecule CEACAM6	Cell surface glycoprotein that plays a role in cell adhesion and tumor progression.
CLCA4	Calcium-activated chloride channel regulator 4	May be involved in mediating calcium-activated chloride conductance.
EDNRA	Endothelin-1 receptor	Receptor for endothelin-1.
GCLC	Glutamate–cysteine ligase catalytic subunit	Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.
GSTM3	Glutathione S-transferase Mu 3	Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
HMOX1	Heme oxygenase 1	Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron.
KCNN4	Intermediate conductance calcium-activated potassium channel protein 4	Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellula…
MIF	Macrophage migration inhibitory factor	Pro-inflammatory cytokine involved in the innate immune response to bacterial pathogens.
SLC8A3	Sodium/calcium exchanger 3	Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
C1QB	Complement C1q subcomponent subunit B	Core component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens t…
ASZ1	Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1	Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
APIP	Methylthioribulose-1-phosphate dehydratase	Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P).
CDH8	Cadherin-8	Cadherins are calcium-dependent cell adhesion proteins.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
MUC20	Mucin-20	May regulate MET signaling cascade.
CEP72	Centrosomal protein of 72 kDa	Involved in the recruitment of key centrosomal proteins to the centrosome.
EHF	ETS homologous factor	Transcriptional activator that may play a role in regulating epithelial cell differentiation and proliferation.
AGTR2	Type-2 angiotensin II receptor	Receptor for angiotensin II, a vasoconstricting peptide.
EPHX1	Epoxide hydrolase 1	Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water.
AHRR	Aryl hydrocarbon receptor repressor	Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation.
FCGR2A	Low affinity immunoglobulin gamma Fc region receptor II-a	Binds to the Fc region of immunoglobulins gamma.
HLA-DRA	HLA class II histocompatibility antigen, DR alpha chain	An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
MBL2	Mannose-binding protein C	Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens t…
MUC4	Mucin-4	Membrane-bound mucin, a family of highly glycosylated proteins that constitute the major component of the mucus, the slimy and viscous secretion covering epithelial surfaces.
PIK3CG	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
PLG	Plasminogen	Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation.

Protein-family classification

Druggable: 20 · Difficult: 2 · Unknown: 21 · Druggable fraction: 0.47

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
Antibody/Immunoglobulin	6	4.1×	0.033
Kinase	3	1.9×	0.673
Enzyme (other)	6	1.7×	0.673
Ion channel	1	2.6×	0.803
Transporter	1	1.8×	0.854
GPCR	2	1.1×	0.902
Protease	1	0.8×	0.995
Other/Unknown	21	0.9×	0.996
Scaffold/PPI	1	0.4×	0.996
Transcription factor	1	0.2×	0.996

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC11A1	Other/Unknown	no		NRAMP_fam
SLC6A14	Other/Unknown	no		Na/ntran_symport, SNS_sf
SLC9A3	Other/Unknown	no		NaH_exchanger, Cation/H_exchanger_TM, Na/H_exchanger_3/5
TGFB1	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb1
SLC26A9	Other/Unknown	no		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
CFTR	Transporter	yes	2.7.4.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, CFTR/ABCC7
HFE	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
STX1A	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
DCTN4	Other/Unknown	no		DCTN4
CEACAM3	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Ig-like_dom_sf
CEACAM6	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
CLCA4	Antibody/Immunoglobulin	yes		VWF_A, CLCA_chordata, CLCA_N
EDNRA	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETA_rcpt
GCLC	Enzyme (other)	yes	6.3.2.2	GCS, Gln_synth/guanido_kin_cat_dom
GSTM3	Enzyme (other)	yes	2.5.1.18	GST_mu, Glutathione_S-Trfase_N, GST_C
HMOX1	Enzyme (other)	yes	1.14.14.18	Haem_Oase, Haem_Oase-like, Haem_Oase-like_multi-hlx
KCNN4	Ion channel	yes		CaM-bd_dom, K_chnl_dom, K_chnl_Ca-activ_SK
MIF	Enzyme (other)	yes	5.3.2.1	Macrophage_inhib_fac, Tautomerase/MIF_sf, Macrophage_inhib_fac_CS
SLC8A3	Other/Unknown	no		Calx_beta, Na_Ca_Ex, NaCa_Exmemb
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
C1QB	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
ASZ1	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
APIP	Enzyme (other)	yes	4.2.1.109	Aldolase_II/adducin_N, MethylthioRu-1-P_deHdtase_MtnB, Salvage_MtnB_euk
CDH8	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
CLN6	Other/Unknown	no		CLN6
MUC20	Other/Unknown	no		MUC20, MUC-20_rpt
CEP72	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, U2A’_phosphoprotein32A_C
EHF	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf
AGTR2	GPCR	yes		ATII_AT2_rcpt, ATII_rcpt, GPCR_Rhodpsn
EPHX1	Enzyme (other)	yes	3.3.2.9	AB_hydrolase_1, Epox_hydrolase-like, Epoxide_hydrolase
AHRR	Transcription factor	no		PAS, bHLH_dom, PAS_fold
FCGR2A	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
CFTR-AS1	Other/Unknown	no
CFTR-AS2	Other/Unknown	no
HLA-DRA	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
MBL2	Other/Unknown	no		C-type_lectin-like, Collagen, C-type_lectin-like/link_sf
MUC4	Other/Unknown	no		EGF, VWF_type-D, NIDO_dom
PIK3CG	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PLG	Protease	yes	3.4.21.7	Kringle, Trypsin_dom, Peptidase_S1A

Expression context

Cohort genes with no expression data: 0.

39 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)	1
broad (>20)	42
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	5
leukocyte	4
olfactory segment of nasal mucosa	4
male germ line stem cell (sensu Vertebrata) in testis	4
primordial germ cell in gonad	4
granulocyte	3
nasal cavity epithelium	3
parotid gland	3
body of pancreas	3
pancreas	3
blood	3
liver	3
right lobe of liver	3
bone marrow	3
right testis	3
right lung	2
palpebral conjunctiva	2
metanephros cortex	2
mucosa of transverse colon	2
sural nerve	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC11A1	204	broad	marker	right lung, upper lobe of left lung, granulocyte
SLC6A14	146	broad	marker	palpebral conjunctiva, nasal cavity epithelium, nasal cavity mucosa
SLC9A3	164	tissue_specific	yes	mucosa of transverse colon, sural nerve, metanephros cortex
TGFB1	204	ubiquitous	marker	granulocyte, monocyte, leukocyte
SLC26A9	151	tissue_specific	marker	parotid gland, left ventricle myocardium, cardiac muscle of right atrium
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas
HFE	238	ubiquitous	marker	type B pancreatic cell, olfactory bulb, stromal cell of endometrium
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood
STX1A	186	ubiquitous	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex
DCTN4	278	ubiquitous	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
CEACAM3	152	tissue_specific	marker	blood, granulocyte, bone marrow
CEACAM6	208	broad	marker	pancreatic ductal cell, palpebral conjunctiva, nasal cavity epithelium
CLCA4	209	tissue_specific	marker	lower esophagus mucosa, colonic mucosa, mucosa of sigmoid colon
EDNRA	253	ubiquitous	marker	cauda epididymis, seminal vesicle, visceral pleura
GCLC	291	ubiquitous	marker	bronchial epithelial cell, right uterine tube, olfactory segment of nasal mucosa
GSTM3	295	ubiquitous	marker	left testis, right testis, adult organism
HMOX1	230	ubiquitous	marker	cartilage tissue, spleen, monocyte
KCNN4	200	ubiquitous	marker	olfactory segment of nasal mucosa, parotid gland, saliva-secreting gland
MIF	147	ubiquitous	marker	pituitary gland, adenohypophysis, cortex of kidney
SLC8A3	168	broad	marker	tibia, gastrocnemius, cortical plate
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
C1QB	266	broad	marker	right lung, spleen, decidua
ASZ1	60	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
APIP	134	ubiquitous	marker	C1 segment of cervical spinal cord, hindlimb stylopod muscle, right adrenal gland
CDH8	188	broad	marker	endothelial cell, Brodmann (1909) area 23, prefrontal cortex
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
CLN6	139	ubiquitous	marker	monocyte, leukocyte, bone marrow
MUC20	185	tissue_specific	marker	right uterine tube, olfactory segment of nasal mucosa, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 23.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
TGFB1	7,596
CHD7	4,819
CHEK2	4,795
TTN	4,237
TSC2	4,135
HMOX1	4,054
SERPINA1	3,617
PLG	3,441
HLA-DRA	3,244

Intra-cohort edges

A	B	Sources
APIP	DCTN4	string_interaction
APIP	EHF	string_interaction
CEACAM3	CEACAM6	string_interaction
CEACAM6	MUC4	string_interaction
CFTR	CLCA4	string_interaction
CFTR	DCTN4	intact
CFTR	EPHX1	intact
CFTR	GSTM3	intact
CFTR	KCNN4	intact
CFTR	MIF	intact
CFTR	SERPINA1	intact
CFTR	SLC26A9	intact, string_interaction
CFTR	SLC9A3	string_interaction
CFTR	TTN	intact
CLN6	STX1A	intact
EPHX1	GSTM3	string_interaction
GCLC	GSTM3	string_interaction
GCLC	HMOX1	string_interaction
HMOX1	SLC6A14	biogrid_interaction
HMOX1	STX1A	intact
MUC20	MUC4	string_interaction
SLC26A9	SLC6A14	string_interaction
SLC26A9	SLC9A3	string_interaction

Structural data

PDB: 29 · AlphaFold-only: 12 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-DRA	P01903	140
MIF	P14174	118
PIK3CG	P48736	107
TTN	Q8WZ42	64
CFTR	P13569	58
PLG	P00747	49
SERPINA1	P01009	46
CHEK2	O96017	38
HMOX1	P09601	26
TGFB1	P01137	20
KCNN4	O15554	17
C1QB	P02746	11
FCGR2A	P12318	9
AGTR2	P50052	7
CEACAM6	P40199	6
EDNRA	P25101	5
CEACAM3	P40198	4
CHD7	Q9P2D1	3
SLC11A1	P49279	2
HFE	Q30201	2
DCTN4	Q9UJW0	2
TSC2	P49815	2
SLC9A3	P48764	1
SLC26A9	Q7LBE3	1
GSTM3	P21266	1
APIP	Q96GX9	1
EHF	Q9NZC4	1
AHRR	A9YTQ3	1
MBL2	P11226	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EPHX1	P07099	95.06
GCLC	P48506	93.68
SLC6A14	Q9UN76	89.48
CLCA4	Q14CN2	89.48
CLN6	Q9NWW5	85.86
STX1A	Q16623	84.94
CDH8	P55286	77.26
SLC8A3	P57103	76.87
ASZ1	Q8WWH4	66.83
CEP72	Q9P209	65.74
MUC20	Q8N307	54.24
MUC4	Q99102

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 256. Enrichment computed across 43 evidence-associated genes (38 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 38 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
R-HSA-425393	4	13.7×	0.042	SLC6A14, SLC9A3, SLC26A9, SLC8A3
Cell surface interactions at the vascular wall	4	10.0×	0.042	TGFB1, CEACAM3, CEACAM6, MIF
Hemostasis	6	5.7×	0.042	TGFB1, SERPINA1, SLC8A3, CEACAM3, CEACAM6, MIF
Innate Immune System	7	4.7×	0.042	SERPINA1, CEACAM3, CEACAM6, MUC20, MBL2, MIF, MUC4
Platelet degranulation	4	9.2×	0.045	TGFB1, SERPINA1, TTN, PLG
Defective GALNT3 causes HFTC	2	37.6×	0.045	MUC20, MUC4
Defective GALNT12 causes CRCS1	2	37.6×	0.045	MUC20, MUC4
Defective C1GALT1C1 causes TNPS	2	35.4×	0.045	MUC20, MUC4
Initial triggering of complement	2	31.6×	0.050	C1QB, MBL2
Immune System	9	3.1×	0.050	TGFB1, SERPINA1, STX1A, CEACAM3, CEACAM6, MUC20, MBL2, MIF (+1 more)
NFE2L2 regulating anti-oxidant/detoxification enzymes	2	28.6×	0.051	GCLC, HMOX1
Termination of O-glycan biosynthesis	2	26.1×	0.056	MUC20, MUC4
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	2	25.0×	0.056	STX1A, HMOX1
Variant SLC6A14 may confer susceptibility towards obesity	1	300.5×	0.060	SLC6A14
Dectin-2 family	2	22.3×	0.060	MUC20, MUC4
SLC-mediated transmembrane transport	4	6.2×	0.060	SLC6A14, SLC9A3, SLC26A9, SLC8A3
Neutrophil degranulation	6	3.6×	0.082	SLC11A1, SERPINA1, CEACAM3, CEACAM6, FCGR2A, MIF
Influenza Virus Induced Apoptosis	1	150.3×	0.085	TGFB1
TGFBR2 MSI Frameshift Mutants in Cancer	1	150.3×	0.085	TGFB1
Defective GCLC causes HAGGSD	1	150.3×	0.085	GCLC
Loss of Function of TGFBR2 in Cancer	1	100.2×	0.106	TGFB1
TGFBR2 Kinase Domain Mutants in Cancer	1	100.2×	0.106	TGFB1
Toxicity of botulinum toxin type C (botC)	1	100.2×	0.106	STX1A
RHO GTPases regulate CFTR trafficking	1	100.2×	0.106	CFTR
C-type lectin receptors (CLRs)	2	12.5×	0.113	MUC20, MUC4
TGFBR1 LBD Mutants in Cancer	1	75.1×	0.122	TGFB1
Ion influx/efflux at host-pathogen interface	1	75.1×	0.122	SLC11A1
Diseases associated with O-glycosylation of proteins	2	11.3×	0.122	MUC20, MUC4
Inhibition of TSC complex formation by AKT (PKB)	1	60.1×	0.130	TSC2
Loss of Function of TGFBR1 in Cancer	1	60.1×	0.130	TGFB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
multicellular organismal-level iron ion homeostasis	3	43.6×	0.030	SLC11A1, HFE, HMOX1
negative regulation of cell-cell adhesion mediated by cadherin	2	76.6×	0.031	TGFB1, PLG
positive regulation of chemokine (C-X-C motif) ligand 2 production	2	76.6×	0.031	TGFB1, MIF
cellular response to follicle-stimulating hormone stimulus	2	70.2×	0.031	EDNRA, GCLC
blood vessel remodeling	3	28.7×	0.031	CHD7, EDNRA, AGTR2
positive regulation of protein secretion	3	25.8×	0.031	TGFB1, TTN, KCNN4
positive regulation of phagocytosis	3	23.9×	0.031	SLC11A1, FCGR2A, MBL2
cellular response to cAMP	3	21.8×	0.031	CFTR, SLC8A3, PIK3CG
positive regulation of cytokine production	3	20.4×	0.033	SLC11A1, MIF, PIK3CG
intracellular iron ion homeostasis	3	18.3×	0.041	SLC11A1, HFE, HMOX1
regulation of systemic arterial blood pressure by circulatory renin-angiotensin	1	421.3×	0.052	AGTR2
columnar/cuboidal epithelial cell maturation	1	421.3×	0.052	TGFB1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1	421.3×	0.052	TGFB1
antigen processing and presentation of peptide or polysaccharide antigen via MHC class II	1	421.3×	0.052	HLA-DRA
right ventricular compact myocardium morphogenesis	1	421.3×	0.052	CHD7
positive regulation of microglia differentiation	1	421.3×	0.052	TGFB1
nitrite transport	1	421.3×	0.052	SLC11A1
regulation of interleukin-23 production	1	421.3×	0.052	TGFB1
branch elongation involved in mammary gland duct branching	1	421.3×	0.052	TGFB1
obsolete positive regulation of prostaglandin secretion involved in immune response	1	421.3×	0.052	MIF
positive regulation of myeloid leukocyte cytokine production involved in immune response	1	421.3×	0.052	MIF
hydrocarbon catabolic process	1	421.3×	0.052	EPHX1
negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I	1	421.3×	0.052	HFE
regulation of protein localization to cell leading edge	1	421.3×	0.052	EDNRA
surfactant homeostasis	2	40.1×	0.052	TGFB1, MBL2
face development	2	40.1×	0.052	CHD7, EDNRA
positive regulation of branching involved in ureteric bud morphogenesis	2	40.1×	0.052	TGFB1, AGTR2
negative regulation of blood vessel endothelial cell migration	2	36.6×	0.052	TGFB1, AGTR2
muscle cell cellular homeostasis	2	32.4×	0.052	TGFB1, PLG
complement activation, classical pathway	2	27.2×	0.052	C1QB, MBL2

Therapeutics

Drugs indicated for this disease

10 approved, 14 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetylcysteine	Approved (phase 4)
Azithromycin	Approved (phase 4)
Aztreonam	Approved (phase 4)
Dornase Alfa	Approved (phase 4)
Ivacaftor	Approved (phase 4)
Lumacaftor	Approved (phase 4)
Mannitol	Approved (phase 4)
Phytonadione	Approved (phase 4)
Tezacaftor	Approved (phase 4)
Tobramycin	Approved (phase 4)
Amikacin	Phase 3 (in late-stage trials)
Ataluren	Phase 3 (in late-stage trials)
Bamocaftor	Phase 3 (in late-stage trials)
Colistin	Phase 3 (in late-stage trials)
Elexacaftor	Phase 3 (in late-stage trials)
Glutathione	Phase 3 (in late-stage trials)
Insulin Aspart	Phase 3 (in late-stage trials)
Insulin Glargine	Phase 3 (in late-stage trials)
Liprotamase	Phase 3 (in late-stage trials)
Pancrelipase	Phase 3 (in late-stage trials)
Prednisone	Phase 3 (in late-stage trials)
Repaglinide	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Somatropin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): .ALPHA.1-PROTEINASE INHIBITOR HUMAN, Alginic Acid, Anakinra, Andecaliximab, Arginine, Brensocatib, Ciprofloxacin, Clarithromycin, Cysteamine, Digitoxin, Doconexent, Ensifentrine, Esomeprazole, Gallium Nitrate, Gentamicin, Glutamine, Glycine, Insulin Detemir, Lenabasum, Linezolid, Losartan, Lucinactant, Miglustat, Minocycline, Mupirocin, Nitric Oxide, Quercetin, Rifampin, Riociguat, Sildenafil, Sitagliptin, Sulfamethoxazole, Trimethoprim, Vancomycin, Vanzacaftor, Vardenafil.

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 9 · Phased (≥1): 12 · Undrugged: 31

Druggability breadth: 23 of 43 evidence-associated genes (53%) 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
SLC9A3	TENAPANOR HYDROCHLORIDE
CFTR	IVACAFTOR
EDNRA	AMBRISENTAN
KCNN4	CLOTRIMAZOLE
MIF	METARAMINOL
CHEK2	NERATINIB
AGTR2	IRBESARTAN
PIK3CG	FEDRATINIB
PLG	AMINOCAPROIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CG	56	4
EDNRA	31	4
CHEK2	30	4
AGTR2	19	4
CFTR	14	4
PLG	11	4
MIF	10	4
SLC9A3	3	4
KCNN4	2	4
EPHX1	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	AGTR2, EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	CHEK2, EDNRA, PIK3CG
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CLOTRIMAZOLE	4	KCNN4
METARAMINOL	4	MIF
IBUDILAST	4	MIF
HEXACHLOROPHENE	4	MIF
HISTAMINE	4	MIF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
PIK3CG	899	Binding:888, ADMET:8, Functional:2, Toxicity:1
CHEK2	690	Binding:687, Functional:2, ADMET:1
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1
PLG	480	Binding:467, ADMET:7, Functional:6
EDNRA	418	Binding:342, Functional:73, Toxicity:2, ADMET:1
AGTR2	244	Binding:188, Functional:56
MIF	205	Binding:202, Functional:3
EPHX1	30	Binding:18, ADMET:12
KCNN4	27	Binding:27
HMOX1	23	Binding:22, ADMET:1
SLC9A3	20	Binding:18, Functional:2
GCLC	14	Binding:14
TGFB1	9	Binding:9
SLC6A14	7	Binding:6, ADMET:1
SLC26A9	4	Binding:3, Functional:1
MBL2	3	Binding:3
SLC11A1	1	Binding:1
GSTM3	1	ADMET:1
TSC2	1	Binding:1
TTN	1	Binding:1
CLN6	1	Binding:1
FCGR2A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase
GCLC	6.3.2.2	glutamate-cysteine ligase
GSTM3	2.5.1.18	glutathione transferase
HMOX1	1.14.14.18	heme oxygenase (biliverdin-producing)
MIF	5.3.2.1, 5.3.3.12	phenylpyruvate tautomerase, L-dopachrome isomerase
TTN	2.7.11.1	non-specific serine/threonine protein kinase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
APIP	4.2.1.109	methylthioribulose 1-phosphate dehydratase
EPHX1	3.3.2.9	microsomal epoxide hydrolase
PIK3CG	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PLG	3.4.21.7	plasmin

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CFTR	520
EDNRA	418
MIF	205
CHEK2	690
AGTR2	244
PIK3CG	899
PLG	480

Pharmacogenomics

Cohort genes with a PharmGKB record: 41; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CFTR	1

Chemical tractability of cohort targets

26 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)
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
GLYBURIDE	4	CFTR
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	AGTR2, EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	CHEK2, EDNRA, PIK3CG
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CLOTRIMAZOLE	4	KCNN4
METARAMINOL	4	MIF
IBUDILAST	4	MIF
HEXACHLOROPHENE	4	MIF
HISTAMINE	4	MIF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	SLC9A3, CFTR, EDNRA, KCNN4, MIF, CHEK2, AGTR2, PIK3CG, PLG
B	Phased (≥1) drug, not yet approved	3	TGFB1, GCLC, EPHX1
C	Druggable family + PDB, no drug	9	HFE, CEACAM3, CEACAM6, GSTM3, HMOX1, TTN, APIP, FCGR2A, HLA-DRA
D	Druggable family + AlphaFold only, no drug	1	CLCA4
E	Difficult family or no structure, no drug	21	SLC11A1, SLC6A14, SLC26A9, SERPINA1, STX1A, DCTN4, SLC8A3, TSC2, C1QB, ASZ1 (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC26A9	4	CFTR
CLCA4	0	CFTR
SLC11A1	1	—
SLC6A14	7	—
HFE	0	—
SERPINA1	0	—
STX1A	0	—
DCTN4	0	—
CEACAM3	0	—
CEACAM6	0	—
GSTM3	1	—
HMOX1	23	—
SLC8A3	0	—
TSC2	1	—
TTN	1	—
C1QB	0	—
ASZ1	0	—
APIP	0	—
CDH8	0	—
CHD7	0	—
CLN6	1	—
MUC20	0	—
CEP72	0	—
EHF	0	—
AHRR	0	—
FCGR2A	1	—
CFTR-AS1	0	—
CFTR-AS2	0	—
HLA-DRA	0	—
MBL2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,429.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	499
PHASE2	175
PHASE3	144
PHASE1	124
PHASE4	79
PHASE1/PHASE2	50
EARLY_PHASE1	15
PHASE2/PHASE3	14

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03921060	PHASE4	RECRUITING	Markers of Osteoporosis in Cystic Fibrosis
NCT04259970	PHASE4	ACTIVE_NOT_RECRUITING	Hyperpolarized Imaging for New Treatments
NCT04467957	PHASE4	ACTIVE_NOT_RECRUITING	Non-contrast Lung Perfusion Mapping Applied for New Insights in Cystic Fibrosis
NCT04602468	PHASE4	ACTIVE_NOT_RECRUITING	Real World Clinical Outcomes With Novel Modulator Therapy Combinations in People With CF (RECOVER)
NCT05517655	PHASE4	RECRUITING	BEGIN Novel ImagiNG Biomarkers
NCT05548283	PHASE4	RECRUITING	Standardizing Treatments for Pulmonary Exacerbations - Aminoglycoside Study
NCT05704036	PHASE4	RECRUITING	Estrogen Supplementation and Bone Health in Women With CF
NCT07148739	PHASE4	RECRUITING	Ensuring Access to Optimal Therapy in CF: The ENACT Study
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IVACAFTOR	4	59
TOBRAMYCIN	4	23
TEZACAFTOR	4	13
ATALUREN	4	11
LUMACAFTOR	4	11
MANNITOL	4	9
VANZACAFTOR	4	9
SORBITOL	4	8
ALENDRONIC ACID	4	7
AMITRIPTYLINE	4	6
CEFTAZIDIME	4	6
DORNASE ALFA	4	5
PANCRELIPASE	4	5
AMIKACIN	4	4
COLISTIMETHATE SODIUM	4	4
ELEXACAFTOR	4	4
ITRACONAZOLE	4	4
AZTREONAM	4	3
LOSARTAN	4	3
MIGLUSTAT	4	3
NITRIC OXIDE	4	3
RIFAMPIN	4	3
.ALPHA.1-PROTEINASE INHIBITOR HUMAN	4	2
AZITHROMYCIN	4	2
CEFTOLOZANE	4	2
COLISTIN	4	2
CYSTEAMINE	4	2
GLYCINE	4	2
INTERFERON GAMMA-1B	4	2
MEROPENEM	4	2