Pulmonary fibrosis

Summary

Pulmonary fibrosis (MONDO:0002771) is a disease (an umbrella term covering 6 Mondo subtypes) with 14 cohort genes (8 GWAS associations across 4 studies) and 203 clinical trials. The dominant Reactome pathway is Telomere Extension By Telomerase (4 cohort genes). Top therapeutic interventions include nintedanib, pirfenidone, and tamoxifen.

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 14
• GWAS associations: 8
• ClinVar variants: 142
• Clinical trials: 203

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary fibrosis
Mondo ID	MONDO:0002771
EFO	EFO:0009448
MeSH	D011658
DOID	DOID:3770
NCIT	C26869
SNOMED CT	51615001
UMLS	C0034069
MedGen	11028
GARD	0023241
Is cancer (heuristic)	no

Also known as: pulmonary interstitial fibrosis

Data availability: 142 ClinVar variants · 8 GWAS associations (4 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › pulmonary fibrosis

Related subtypes (13): bronchiolitis obliterans syndrome, pneumoconiosis, pulmonary fibrosis-hepatic hyperplasia-bone marrow hypoplasia syndrome, interstitial lung disease specific to childhood, isolated pulmonary capillaritis, interstitial lung disease specific to adulthood, drug or radiation exposure-related interstitial lung disease, hypersensitivity pneumonitis, secondary pulmonary hemosiderosis, inherited interstitial lung disease, radiation pneumonitis, bronchiolocentric pattern of interstitial pneumonia, idiopathic pulmonary fibrosis

Subtypes (6): pulmonary fibrosis and/or bone marrow failure, telomere-related, postinflammatory pulmonary fibrosis, diffuse pulmonary fibrosis, localized pulmonary fibrosis, tuberculous fibrosis of lung, graphite pneumoconiosis

Genetics & variants

GWAS landscape

8 GWAS associations across 4 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs35705950	2e-65	MUC5AC - MUC5B	T	1.12
rs10069690	2e-14	TERT	T	0.31
rs3737040	7e-10	STARD13 - RFC3	?
rs116483731	6e-09	SPDL1	A	0.91
rs12084421	9e-09	MIPEPP2 - CHRM3	T	0.8
rs13243708	2e-08	ZKSCAN1	C	0.2
rs6631122	3e-08	CKS1BP6 - FTLP2	G	0.16
rs2957316	5e-08	MAPK8IP1P1 - ARL17B	C	0.28

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90018908	Sakaue S	2021	1,566	467,560	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90651293	Liu TY	2025	592	224,406	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90044079	Jiang L	2021	363	455,985	A generalized linear mixed model association tool for biobank-scale data.
GCST90018688	Sakaue S	2021	126	176,974	A cross-population atlas of genetic associations for 220 human phenotypes.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	7
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	4
splice_region_variant	1
non_coding_transcript_exon_variant	1
missense_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs35705950	11	1219991	G>A,T	0.05	splice_region_variant	MUC5AC - MUC5B	2e-65	Tier 2: splice/UTR
rs10069690	5	1279675	C>T	0.05	intron_variant	TERT	2e-14	Tier 4: intronic/intergenic
rs3737040	13	33610800	A>G	0.05	non_coding_transcript_exon_variant	STARD13 - RFC3	7e-10	Tier 4: intronic/intergenic
rs116483731	5	169588475	G>A,T		missense_variant	SPDL1	6e-09	Tier 1: coding
rs12084421	1	239151718	C>T	0.323	intron_variant	MIPEPP2 - CHRM3	9e-09	Tier 4: intronic/intergenic
rs13243708	7	100018668	T>A,C,G	0.05	intron_variant	ZKSCAN1	2e-08	Tier 4: intronic/intergenic
rs6631122	X	30621617	T>A,G	0.05	intergenic_variant	CKS1BP6 - FTLP2	3e-08	Tier 4: intronic/intergenic
rs2957316	17	46253848	T>C	0.05	intron_variant	MAPK8IP1P1 - ARL17B	5e-08	Tier 4: intronic/intergenic

ClinVar germline variants

142 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 39 likely risk allele, 20 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 14 pathogenic, 6 likely pathogenic, 3 pathogenic/likely risk allele, 2 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1695953	NM_002582.4(PARN):c.656G>A (p.Trp219Ter)	PARN	Pathogenic	criteria provided, single submitter
1695961	NM_002582.4(PARN):c.781C>T (p.Gln261Ter)	PARN	Pathogenic	criteria provided, single submitter
190468	NM_002582.4(PARN):c.246-2A>G	PARN	Pathogenic	criteria provided, single submitter
190469	NM_002582.4(PARN):c.529C>T (p.Gln177Ter)	PARN	Pathogenic	criteria provided, multiple submitters, no conflicts
190470	NM_002582.4(PARN):c.563dup (p.Glu189fs)	PARN	Pathogenic	criteria provided, single submitter
2942751	NM_002582.4(PARN):c.1481-1G>A	PARN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834007	NM_002582.4(PARN):c.1257del (p.Phe419fs)	PARN	Pathogenic	criteria provided, single submitter
977495	NM_002582.4(PARN):c.1749_1750del (p.Glu585fs)	PARN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072324	NM_001283009.2(RTEL1):c.329_332del (p.Ile110fs)	RTEL1	Pathogenic	criteria provided, single submitter
1695936	NM_001283009.2(RTEL1):c.1596-2A>G	RTEL1	Pathogenic	no assertion criteria provided
1695939	NM_001283009.2(RTEL1):c.699+1G>T	RTEL1	Pathogenic	criteria provided, single submitter
1904651	NM_001283009.2(RTEL1):c.1910del (p.Asn637fs)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190472	NM_001283009.2(RTEL1):c.602del (p.Gly201fs)	RTEL1	Pathogenic/Likely risk allele	no assertion criteria provided
190475	NM_001283009.2(RTEL1):c.3371A>C (p.His1124Pro)	RTEL1	Pathogenic/Likely risk allele	no assertion criteria provided
253011	NM_001283009.2(RTEL1):c.2005C>T (p.Gln669Ter)	RTEL1	Pathogenic	criteria provided, single submitter
42020	NM_001283009.2(RTEL1):c.2920C>T (p.Arg974Ter)	RTEL1	Pathogenic	criteria provided, multiple submitters, no conflicts
65417	NM_001283009.2(RTEL1):c.2956C>T (p.Arg986Ter)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436599	NM_001283009.2(RTEL1):c.1135+1G>A	RTEL1-TNFRSF6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13199	NM_001098668.4(SFTPA2):c.692G>T (p.Gly231Val)	SFTPA2	Pathogenic/Likely risk allele	no assertion criteria provided
13208	NM_001317778.2(SFTPC):c.218T>C (p.Ile73Thr)	SFTPC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12736	NM_198253.3(TERT):c.2594G>A (p.Arg865His)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12737	NM_198253.3(TERT):c.2240del (p.Val747fs)	TERT	Pathogenic	criteria provided, single submitter
1686800	NM_198253.3(TERT):c.2583-2A>T	TERT	Pathogenic/Likely pathogenic	criteria provided, single submitter
242683	NM_198253.3(TERT):c.2599G>A (p.Val867Met)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29899	NM_198253.3(TERT):c.1892G>A (p.Arg631Gln)	TERT	Pathogenic	criteria provided, multiple submitters, no conflicts
39108	NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410651	NM_198253.3(TERT):c.336dup (p.Glu113fs)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410693	NM_198253.3(TERT):c.2011C>T (p.Arg671Trp)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523957	NM_198253.3(TERT):c.2991del (p.Cys998fs)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
539192	NM_198253.3(TERT):c.1048_1049del (p.Leu350fs)	TERT	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 34 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TINF2	Moderate	Autosomal dominant	pulmonary fibrosis	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TINF2	Orphanet:1775	Dyskeratosis congenita
TINF2	Orphanet:3088	Revesz syndrome
TINF2	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
SFTPA2	Orphanet:2032	Idiopathic pulmonary fibrosis
SFTPC	Orphanet:2032	Idiopathic pulmonary fibrosis
SFTPC	Orphanet:217566	Chronic respiratory distress with surfactant metabolism deficiency
SFTPC	Orphanet:440392	Interstitial lung disease due to SP-C deficiency
SFTPC	Orphanet:685082	Pediatric acute respiratory distress syndrome
TERC	Orphanet:1775	Dyskeratosis congenita
TERC	Orphanet:2032	Idiopathic pulmonary fibrosis
TERC	Orphanet:88	Idiopathic aplastic anemia
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TNIP1	Orphanet:536	Systemic lupus erythematosus
KIF15	Orphanet:261323	21q22.11q22.12 microdeletion syndrome
FAM111B	Orphanet:221043	Hereditary fibrosing poikiloderma-tendon contractures-myopathy-pulmonary fibrosis syndrome
DKC1	Orphanet:1775	Dyskeratosis congenita
DKC1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
MUC5B	Orphanet:171700	Diffuse panbronchiolitis
MUC5B	Orphanet:2032	Idiopathic pulmonary fibrosis
MUC5B	Orphanet:686465	Fibrotic hypersensitivity pneumonitis
PARN	Orphanet:1775	Dyskeratosis congenita
PARN	Orphanet:2032	Idiopathic pulmonary fibrosis
PARN	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

14 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TINF2	HGNC:11824	ENSG00000092330	Q9BSI4	TERF1-interacting nuclear factor 2	gencc,clinvar
SFTPA2	HGNC:10799	ENSG00000185303	Q8IWL1	Pulmonary surfactant-associated protein A2	clinvar
SFTPC	HGNC:10802	ENSG00000168484	P11686	Surfactant protein C	clinvar
TERC	HGNC:11727	ENSG00000270141		telomerase RNA component	clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
TNIP1	HGNC:16903	ENSG00000145901	Q15025	TNFAIP3-interacting protein 1	clinvar
KIF15	HGNC:17273	ENSG00000163808	Q9NS87	Kinesin-like protein KIF15	clinvar
FAM111B	HGNC:24200	ENSG00000189057	Q6SJ93	Serine protease FAM111B	clinvar
NAF1	HGNC:25126	ENSG00000145414	Q96HR8	H/ACA ribonucleoprotein complex non-core subunit NAF1	clinvar
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	clinvar
RTEL1-TNFRSF6B	HGNC:44095	ENSG00000026036		RTEL1-TNFRSF6B readthrough (NMD candidate)	clinvar
MUC5B	HGNC:7516	ENSG00000117983	Q9HC84	Mucin-5B	clinvar
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TINF2	TERF1-interacting nuclear factor 2	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
SFTPA2	Pulmonary surfactant-associated protein A2	In presence of calcium ions, it binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung and is essential for normal respiration.
SFTPC	Surfactant protein C	Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
TNIP1	TNFAIP3-interacting protein 1	Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG.
KIF15	Kinesin-like protein KIF15	Plus-end directed kinesin-like motor enzyme involved in mitotic spindle assembly.
FAM111B	Serine protease FAM111B	Serine protease.
NAF1	H/ACA ribonucleoprotein complex non-core subunit NAF1	RNA-binding protein required for the maturation of box H/ACA snoRNPs complex and ribosome biogenesis.
DKC1	H/ACA ribonucleoprotein complex subunit DKC1	Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA.
MUC5B	Mucin-5B	Gel-forming mucin that is thought to contribute to the lubricating and viscoelastic properties of whole saliva and cervical mucus.
PARN	Poly(A)-specific ribonuclease PARN	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 13 · Druggable fraction: 0.07

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
Other/Unknown	13	1.7×	0.007
Protease	1	2.6×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TINF2	Other/Unknown	no		TINF2_N, TINF2
SFTPA2	Other/Unknown	no		C-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
SFTPC	Other/Unknown	no		SP-C, BRICHOS_dom, Surfactant_protein_propep
TERC	Other/Unknown	no
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
TNIP1	Other/Unknown	no
KIF15	Other/Unknown	no		Kinesin_motor_dom, P-loop_NTPase, HMMR_C
FAM111B	Protease	yes		Peptidase_S1_PA,
NAF1	Other/Unknown	no		H/ACA_rnp_Gar1/Naf1, Transl_B-barrel_sf, Gar1/Naf1_Cbf5-bd_sf
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451
RTEL1-TNFRSF6B	Other/Unknown	no
MUC5B	Other/Unknown	no		VWF_dom, VWF_type-D, TIL_dom
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

11 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult organism	2
lower lobe of lung	2
male germ line stem cell (sensu Vertebrata) in testis	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
sural nerve	2
ganglionic eminence	2
secondary oocyte	2
granulocyte	1
right adrenal gland	1
right adrenal gland cortex	1
visceral pleura	1
right lung	1
bone marrow cell	1
colonic epithelium	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
blood	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TINF2	144	ubiquitous	marker	granulocyte, right adrenal gland, right adrenal gland cortex
SFTPA2	159	tissue_specific	marker	lower lobe of lung, adult organism, visceral pleura
SFTPC	208	tissue_specific	marker	lower lobe of lung, right lung, adult organism
TERC	113	ubiquitous	yes	bone marrow cell, colonic epithelium, male germ line stem cell (sensu Vertebrata) in testis
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
TNIP1	298	ubiquitous	marker	lower esophagus mucosa, blood, hindlimb stylopod muscle
KIF15	133	ubiquitous	marker	ventricular zone, ganglionic eminence, left testis
FAM111B	140	ubiquitous	marker	secondary oocyte, buccal mucosa cell, ganglionic eminence
NAF1	245	ubiquitous	marker	tibial artery, popliteal artery, gastrocnemius
DKC1	287	ubiquitous	marker	secondary oocyte, sural nerve, gingival epithelium
RTEL1-TNFRSF6B	135		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum
MUC5B	171	tissue_specific	marker	trachea, gall bladder, mucosa of transverse colon
PARN	134	ubiquitous	marker	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
DKC1	4,882
TNIP1	3,304
MUC5B	2,659
RTEL1	2,324
KIF15	2,063
TINF2	1,769
SFTPC	1,613
PARN	1,532
NAF1	1,446

Intra-cohort edges

A	B	Sources
DKC1	NAF1	biogrid_interaction, intact, string_interaction
DKC1	PARN	string_interaction
DKC1	RTEL1	string_interaction
DKC1	TERT	intact, string_interaction
DKC1	TINF2	string_interaction
MUC5B	SFTPC	string_interaction
NAF1	RTEL1	string_interaction
NAF1	TERT	string_interaction
NAF1	TINF2	string_interaction
PARN	RTEL1	string_interaction
PARN	TINF2	string_interaction
RTEL1	TERT	string_interaction
RTEL1	TINF2	string_interaction
TERT	TINF2	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 2 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
TNIP1	Q15025	8
DKC1	O60832	7
KIF15	Q9NS87	4
TINF2	Q9BSI4	3
SFTPC	P11686	3
RTEL1	Q9NZ71	3
PARN	O95453	3
MUC5B	Q9HC84	2
NAF1	Q96HR8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SFTPA2	Q8IWL1	84.09
FAM111B	Q6SJ93	69.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 79. Enrichment computed across 14 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Telomere Extension By Telomerase	4	182.7×	3e-07	TINF2, TERT, RTEL1, DKC1
Defective CSF2RB causes SMDP5	2	326.3×	4e-04	SFTPA2, SFTPC
Defective CSF2RA causes SMDP4	2	326.3×	4e-04	SFTPA2, SFTPC
Extension of Telomeres	2	120.2×	0.002	TERT, RTEL1
Telomere Maintenance	2	73.7×	0.004	TERT, RTEL1
Surfactant metabolism	2	73.7×	0.004	SFTPA2, SFTPC
Defective SFTPA2 causes IPF	1	1142.0×	0.008	SFTPA2
Defective pro-SFTPC causes SMDP2 and RDS	1	1142.0×	0.008	SFTPC
Chromosome Maintenance	2	42.3×	0.008	TERT, RTEL1
Diseases associated with surfactant metabolism	1	285.5×	0.028	SFTPA2
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	163.1×	0.043	TERT
Diseases of metabolism	2	16.1×	0.043	SFTPA2, MUC5B
Telomere C-strand synthesis initiation	1	81.6×	0.054	TINF2
Processive synthesis on the C-strand of the telomere	1	76.1×	0.054	TINF2
Telomere C-strand (Lagging Strand) Synthesis	1	76.1×	0.054	TINF2
Cytosolic iron-sulfur cluster assembly	1	76.1×	0.054	RTEL1
Defective GALNT3 causes HFTC	1	71.4×	0.054	MUC5B
Defective GALNT12 causes CRCS1	1	71.4×	0.054	MUC5B
Signal regulatory protein family interactions	1	67.2×	0.054	SFTPA2
Defective C1GALT1C1 causes TNPS	1	67.2×	0.054	MUC5B
Removal of the Flap Intermediate from the C-strand	1	63.4×	0.054	TINF2
KSRP (KHSRP) binds and destabilizes mRNA	1	63.4×	0.054	PARN
Resolution of D-Loop Structures	1	63.4×	0.054	RTEL1
Regulation of TLR by endogenous ligand	1	49.6×	0.063	SFTPA2
Termination of O-glycan biosynthesis	1	49.6×	0.063	MUC5B
Deadenylation of mRNA	1	43.9×	0.066	PARN
Polymerase switching on the C-strand of the telomere	1	42.3×	0.066	TINF2
Dectin-2 family	1	42.3×	0.066	MUC5B
ATF4 activates genes in response to endoplasmic reticulum stress	1	40.8×	0.066	PARN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	39.4×	0.066	RTEL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomerase RNA stabilization	3	1053.2×	1e-07	NAF1, DKC1, PARN
box H/ACA sno(s)RNA 3’-end processing	2	1404.3×	2e-05	DKC1, PARN
positive regulation of telomere maintenance via telomerase	3	183.2×	2e-05	NAF1, DKC1, PARN
regulation of telomerase RNA localization to Cajal body	2	702.2×	7e-05	DKC1, PARN
positive regulation of telomere maintenance via telomere lengthening	2	468.1×	1e-04	RTEL1, NAF1
telomerase holoenzyme complex assembly	2	468.1×	1e-04	NAF1, DKC1
telomere maintenance via telomerase	2	122.1×	0.002	TERT, DKC1
respiratory gaseous exchange by respiratory system	2	104.0×	0.002	SFTPA2, SFTPC
positive regulation of telomere maintenance	2	85.1×	0.003	TINF2, RTEL1
DNA strand displacement	1	1404.3×	0.004	RTEL1
RNA-templated transcription	1	1404.3×	0.004	TERT
DNA strand elongation	1	1404.3×	0.004	TERT
siRNA transcription	1	1404.3×	0.004	TERT
positive regulation of transdifferentiation	1	1404.3×	0.004	TERT
regulation of telomere maintenance via telomere lengthening	1	1404.3×	0.004	TINF2
negative regulation of telomere maintenance in response to DNA damage	1	1404.3×	0.004	RTEL1
positive regulation of telomeric loop disassembly	1	1404.3×	0.004	RTEL1
telomere maintenance	2	44.6×	0.005	TERT, RTEL1
box H/ACA snoRNP assembly	1	702.2×	0.005	NAF1
RNA-templated DNA biosynthetic process	1	702.2×	0.005	TERT
RNA modification	1	702.2×	0.005	PARN
positive regulation of hair cycle	1	702.2×	0.005	TERT
telomeric loop disassembly	1	702.2×	0.005	RTEL1
lncRNA processing	1	702.2×	0.005	PARN
protein localization to Cajal body	1	702.2×	0.005	DKC1
priRNA 3’-end processing	1	702.2×	0.005	PARN
siRNA 3’-end processing	1	702.2×	0.005	PARN
snoRNA guided rRNA pseudouridine synthesis	1	468.1×	0.007	NAF1
snRNA pseudouridine synthesis	1	468.1×	0.007	DKC1
centrosome separation	1	468.1×	0.007	KIF15

Therapeutics

Drugs indicated for this disease

0 approved, 6 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetylcysteine	Phase 3 (in late-stage trials)
Admilparant	Phase 3 (in late-stage trials)
Azathioprine	Phase 3 (in late-stage trials)
INTERFERON GAMMA-1B	Phase 3 (in late-stage trials)
Nintedanib	Phase 3 (in late-stage trials)
Treprostinil	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bevacizumab, Dapsone, Dexamethasone, Etanercept, Interferon Alfa, Oxygen, Pirfenidone, Pomalidomide, Prednisone.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 11

Druggability breadth: 5 of 14 evidence-associated genes (36%) 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
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
NAF1	1	2
DKC1	1	2
TINF2	0	0
SFTPA2	0	0
SFTPC	0	0
TERC	0	0
RTEL1	0	0
TNIP1	0	0
KIF15	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
MOLIBRESIB	2	DKC1, NAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
KIF15	20	Binding:20
DKC1	8	Binding:8
NAF1	7	Binding:7
PARN	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
MOLIBRESIB	2	DKC1, NAF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TERT
B	Phased (≥1) drug, not yet approved	2	NAF1, DKC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	FAM111B
E	Difficult family or no structure, no drug	10	TINF2, SFTPA2, SFTPC, TERC, RTEL1, TNIP1, KIF15, RTEL1-TNFRSF6B, MUC5B, PARN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TINF2	0	—
SFTPA2	0	—
SFTPC	0	—
TERC	0	—
RTEL1	0	—
TNIP1	0	—
KIF15	20	—
FAM111B	0	—
RTEL1-TNFRSF6B	0	—
MUC5B	0	—
PARN	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 203.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	118
PHASE2	33
PHASE3	20
PHASE1	13
PHASE2/PHASE3	8
PHASE1/PHASE2	6
EARLY_PHASE1	3
PHASE4	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07570888	PHASE4	NOT_YET_RECRUITING	This is a Trial Designed to Evaluate the Combination of Nerandomilast With Mycophenolate Across a Wide Variety of Pulmonary Fibrosis Subtypes, With the Aim of Providing Clinicians With Assurance That This is an Appropriate Therapeutic Combination.
NCT04619680	PHASE4	COMPLETED	The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
NCT04905693	PHASE3	ENROLLING_BY_INVITATION	Extension Study of Inhaled Treprostinil in Subjects With Fibrotic Lung Disease
NCT04948203	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Assessing the Efficacy of Sirolimus in Patients With COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis
NCT05943535	PHASE3	RECRUITING	Study of the Efficacy and Safety of Inhaled Treprostinil in Subjects With Progressive Pulmonary Fibrosis (TETON-PPF)
NCT06025578	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of BMS-986278 in Participants With Progressive Pulmonary Fibrosis
NCT06238622	PHASE3	RECRUITING	A Follow-up Study to Test Long-term Treatment With Nerandomilast in People With Pulmonary Fibrosis Who Took Part in a Previous Study With Nerandomilast
NCT07201922	PHASE3	RECRUITING	A Study to Test Whether Nerandomilast Can Help Slow Down Changes in the Lung in People With a Family History of Pulmonary Fibrosis
NCT07441408	PHASE3	NOT_YET_RECRUITING	Long-term Extension Study to Evaluate Safety and Tolerability of Admilparant in Participants With Pulmonary Fibrosis
NCT07503587	PHASE3	NOT_YET_RECRUITING	Evaluating the Efficacy and Safety of of HSK44459 in People With Progressive Pulmonary Fibrosis
NCT00004563	PHASE3	COMPLETED	Scleroderma Lung Disease
NCT00052039	PHASE3	TERMINATED	A Randomized, Double-Blind, Three-Arm, Phase 3b Study Comparing the Safety and Efficacy of Interferon Gamma-1b With Azathioprine, and Azathioprine Alone in Patients With IPF Receiving Prednisone
NCT00070590	PHASE2/PHASE3	COMPLETED	Efficacy and Safety of Oral Bosentan in Pulmonary Fibrosis Associated With Scleroderma
NCT00075998	PHASE3	TERMINATED	The INSPIRE Trial: A Study of Interferon Gamma-1b for Idiopathic Pulmonary Fibrosis (IPF)
NCT00076635	PHASE3	TERMINATED	An Open-Label Study of the Safety of Interferon Gamma-1b in Patients With IPF
NCT00131274	PHASE2/PHASE3	COMPLETED	Gleevec Idiopathic Pulmonary Fibrosis (IPF) Study
NCT00439543	PHASE2/PHASE3	UNKNOWN	Trial of Iloprost in Pulmonary Hypertension Secondary to Pulmonary Fibrosis
NCT00517933	PHASE3	COMPLETED	Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis
NCT00639496	PHASE3	COMPLETED	Study of the Effects of High-dose N-acetylcysteine (NAC) in Idiopathic Pulmonary Fibrosis (IPF)
NCT00650091	PHASE3	COMPLETED	Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF
NCT00896155	PHASE3	UNKNOWN	Trial of Concurrent Versus Sequential Tamoxifen With Radiotherapy in Breast Cancer Patients
NCT00981747	PHASE2/PHASE3	TERMINATED	Targeting Vascular Reactivity in Idiopathic Pulmonary Fibrosis
NCT01335464	PHASE3	COMPLETED	Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients
NCT01335477	PHASE3	COMPLETED	Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II
NCT01570764	PHASE3	COMPLETED	Cyclophosphamide Systemic Sclerosis Associated Interstitial Lung Disease
NCT02496182	PHASE2/PHASE3	UNKNOWN	Pirfenidone in the Chronic Hypersensitivity Pneumonitis Treatment
NCT03267108	PHASE3	TERMINATED	A Study to Assess Pulsed Inhaled Nitric Oxide in Subjects With Pulmonary Fibrosis at Risk for Pulmonary Hypertension
NCT04274257	PHASE2/PHASE3	COMPLETED	A Study of the Efficacy and Safety of Rituximab in Participants With Systemic Sclerosis
NCT04979884	PHASE3	COMPLETED	Safety and Effectiveness of Cyclosporin in the Management of COVID19 ARDS Patients in Alexandria University Hospital
NCT05516550	PHASE2/PHASE3	UNKNOWN	Study to Assess Efficacy and Safety of Treamid for Patients With Reduced Exercise Tolerance After COVID-19
NCT05241275	PHASE2	ACTIVE_NOT_RECRUITING	Xenon MRI and Progressive ILD
NCT06189820	PHASE2	RECRUITING	Role of the Fibroblast Activation Protein (FAP) as Biomarker of Fibrotic Lung Diseases
NCT06329401	PHASE2	RECRUITING	A Study Evaluating the Safety and Efficacy of Inhaled AP01 in Participants With Progressive Pulmonary Fibrosis
NCT06532071	PHASE2	RECRUITING	Advanced Imaging for Pulmonary Fibrosis
NCT06951217	PHASE2	RECRUITING	An Extension Study of Subjects Who Received an Avalyn Inhaled Antifibrotic Agent (SAIL)
NCT07464132	PHASE1/PHASE2	RECRUITING	Application of [68Ga]Ga-NI-FAPI-04 PET/CT Imaging in Fibroblast Activation Protein Related Diseases
NCT07572383	PHASE2	RECRUITING	Advanced Imaging to Assess the Effect of Immunosuppression on Progressive Fibrosis
NCT00000596	PHASE2	COMPLETED	Diffuse Fibrotic Lung Disease
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT00052052	PHASE2	COMPLETED	An Open-Label Study of the Safety and Efficacy of Subcutaneous Recombinant Interferon-Gamma 1b (IFN-Gamma 1b) in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NINTEDANIB	4	8
PIRFENIDONE	4	5
TAMOXIFEN	4	3
TREPROSTINIL	4	3
ACETYLCYSTEINE	4	2
GADOTERATE MEGLUMINE	4	2
AZATHIOPRINE	4	1
BOSENTAN	4	1
COLCHICINE	4	1
DANAZOL	4	1
DAPSONE	4	1
ERYTHROMYCIN	4	1
ILOPROST	4	1
INTERFERON GAMMA-1B	4	1
POMALIDOMIDE	4	1
PRAVASTATIN	4	1
XENON XE-129, HYPERPOLARIZED	4	1
ZILEUTON	4	1
ADMILPARANT	3	3
INTERFERON GAMMA-1A	3	3
INTERFERON	3	1
NERANDOMILAST	2	2
CC-90001	2	1
FAPI GA-68	2	1
TANZISERTIB	2	1
TREAMID	2	1
CHEMBL5435500	0	3
CHEMBL4792718	0	1
CHEMBL5439651	0	1
CHEMBL2093113	0	1