Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

Summary

Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6 (MONDO:0030690) is a disease caused by RPA1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RPA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary fibrosis and/or bone marrow failure, telomere-related, 6
Mondo ID	MONDO:0030690
OMIM	619767
UMLS	C5676927
MedGen	1805650
GARD	0025613
Is cancer (heuristic)	no

Also known as: PFBMFT6 · pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

Data availability: 6 ClinVar variants · 2 GenCC gene-disease records.

Disease family

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 › pulmonary fibrosis and/or bone marrow failure, telomere-related › pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

Related subtypes (8): pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, pulmonary fibrosis and/or bone marrow failure, telomere-related, 5, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342931	NM_002945.5(RPA1):c.718G>A (p.Glu240Lys)	RPA1	Pathogenic	no assertion criteria provided
1342932	NM_002945.5(RPA1):c.680T>C (p.Val227Ala)	RPA1	Pathogenic	no assertion criteria provided
1327121	NM_002945.5(RPA1):c.808A>G (p.Thr270Ala)	RPA1	Uncertain significance	criteria provided, single submitter
3234891	NM_002945.5(RPA1):c.1313G>A (p.Ser438Asn)	RPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4079891	NM_002945.5(RPA1):c.1057G>A (p.Gly353Arg)	RPA1	Uncertain significance	criteria provided, single submitter
4531641	NM_002945.5(RPA1):c.442A>G (p.Ser148Gly)	RPA1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
POLR1A	Strong	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	9
RPA1	Strong	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLR1A	Orphanet:1200	Burn-McKeown syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPA1	HGNC:10289	ENSG00000132383	P27694	Replication protein A 70 kDa DNA-binding subunit	gencc,clinvar
POLR1A	HGNC:17264	ENSG00000068654	O95602	DNA-directed RNA polymerase I subunit RPA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPA1	Replication protein A 70 kDa DNA-binding subunit	As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress.
POLR1A	DNA-directed RNA polymerase I subunit RPA1	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPA1	Other/Unknown	no		NA-bd_OB_tRNA, Rfa1, Rep_factor-A_N
POLR1A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
ventricular zone	1
stromal cell of endometrium	1
sural nerve	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPA1	300	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
POLR1A	198	ubiquitous	marker	sural nerve, tibialis anterior, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPA1	6,988
POLR1A	4,620

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPA1	P27694	42
POLR1A	O95602	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	407.9×	0.012	RPA1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	407.9×	0.012	RPA1
Removal of the Flap Intermediate	1	407.9×	0.012	RPA1
Translesion synthesis by REV1	1	356.9×	0.012	RPA1
Translesion synthesis by POLI	1	335.9×	0.012	RPA1
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.012	RPA1
Translesion synthesis by POLK	1	317.2×	0.012	RPA1
Translesion Synthesis by POLH	1	300.5×	0.012	RPA1
PCNA-Dependent Long Patch Base Excision Repair	1	259.6×	0.012	RPA1
Gap-filling DNA repair synthesis and ligation in GG-NER	1	219.6×	0.012	RPA1
Recognition of DNA damage by PCNA-containing replication complex	1	190.3×	0.012	RPA1
HSF1 activation	1	190.3×	0.012	RPA1
Positive epigenetic regulation of rRNA expression	1	173.0×	0.012	POLR1A
Termination of translesion DNA synthesis	1	173.0×	0.012	RPA1
Activation of the pre-replicative complex	1	163.1×	0.012	RPA1
RNA Polymerase I Transcription Termination	1	163.1×	0.012	POLR1A
Impaired BRCA2 binding to RAD51	1	154.3×	0.012	RPA1
Activation of ATR in response to replication stress	1	150.3×	0.012	RPA1
HDR through Single Strand Annealing (SSA)	1	146.4×	0.012	RPA1
RNA Polymerase I Promoter Clearance	1	146.4×	0.012	POLR1A
RNA Polymerase I Transcription	1	142.8×	0.012	POLR1A
Fanconi Anemia Pathway	1	139.3×	0.012	RPA1
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.012	RPA1
Negative epigenetic regulation of rRNA expression	1	129.8×	0.012	POLR1A
Dual Incision in GG-NER	1	129.8×	0.012	RPA1
Formation of Incision Complex in GG-NER	1	126.9×	0.012	RPA1
RNA Polymerase I Transcription Initiation	1	112.0×	0.014	POLR1A
HDR through Homologous Recombination (HRR)	1	95.2×	0.015	RPA1
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.016	RPA1
Dual incision in TC-NER	1	86.5×	0.016	RPA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of protein localization to nucleolus	1	2808.7×	0.004	POLR1A
protein localization to chromosome	1	2106.5×	0.004	RPA1
nucleolar large rRNA transcription by RNA polymerase I	1	1685.2×	0.004	POLR1A
transcription by RNA polymerase I	1	702.2×	0.007	POLR1A
protein localization to site of double-strand break	1	526.6×	0.008	RPA1
telomere maintenance via telomerase	1	366.4×	0.009	RPA1
mismatch repair	1	324.1×	0.009	RPA1
DNA-templated DNA replication	1	280.9×	0.009	RPA1
base-excision repair	1	234.1×	0.009	RPA1
homeostasis of number of cells within a tissue	1	221.7×	0.009	RPA1
nucleotide-excision repair	1	191.5×	0.010	RPA1
DNA recombination	1	168.5×	0.010	RPA1
telomere maintenance	1	133.8×	0.011	RPA1
hemopoiesis	1	133.8×	0.011	RPA1
meiotic cell cycle	1	122.1×	0.011	RPA1
DNA replication	1	82.6×	0.016	RPA1
double-strand break repair via homologous recombination	1	78.0×	0.016	RPA1
in utero embryonic development	1	36.0×	0.032	RPA1
DNA repair	1	31.9×	0.034	RPA1
DNA damage response	1	26.8×	0.039	RPA1
positive regulation of cell population proliferation	1	16.8×	0.059	RPA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLR1A	1	2
RPA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	POLR1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RPA1	28	Binding:28
POLR1A	16	Binding:16

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	POLR1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	POLR1A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RPA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RPA1	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.