Diamond-Blackfan anemia 1

Summary

Diamond-Blackfan anemia 1 (MONDO:0007110) is a disease caused by RPS19 (GenCC Definitive), with 5 cohort genes and 1 clinical trial. Top therapeutic interventions include leucine.

At a glance

• Causal gene: RPS19 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 97
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Diamond-Blackfan anemia 1
Mondo ID	MONDO:0007110
MeSH	C567302
OMIM	105650
DOID	DOID:0111895
NCIT	C176911
UMLS	C2676137
MedGen	390966
GARD	0015039
Is cancer (heuristic)	no

Also known as: DBA · DBA1 · Diamond-Blackfan anaemia caused by mutation in RPS19 · Diamond-Blackfan Anaemia type 1 · Diamond-Blackfan anemia 1 · Diamond-Blackfan anemia caused by mutation in RPS19 · Diamond-Blackfan Anemia type 1 · RPS19 Diamond-Blackfan anaemia · RPS19 Diamond-Blackfan anemia

Data availability: 97 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › pure red-cell aplasia › Diamond-Blackfan anemia › Diamond-Blackfan anemia 1

Related subtypes (21): Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, Diamond-Blackfan anemia 2, Diamond-Blackfan anemia 15 with mandibulofacial dysostosis, Diamond-Blackfan anemia 3, Diamond-Blackfan anemia 4, Diamond-Blackfan anemia 5, Diamond-Blackfan anemia 6, Diamond-Blackfan anemia 7, Diamond-Blackfan anemia 8, Diamond-Blackfan anemia 9, Diamond-Blackfan anemia 10, Diamond-Blackfan anemia 11, Diamond-Blackfan anemia 12, Diamond-Blackfan anemia 13, Diamond-Blackfan anemia 21, Diamond-Blackfan anemia 18, Diamond-Blackfan anemia 19, Diamond-Blackfan anemia 20, Diamond-Blackfan anemia 16, Diamond-Blackfan anemia 17, Diamond-Blackfan anemia 22

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

97 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 22 pathogenic, 10 likely benign, 10 conflicting classifications of pathogenicity, 7 benign, 7 likely pathogenic, 6 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6318	NM_001022.4(RPS19):c.[134_135inv;138_139dup]		Pathogenic	no assertion criteria provided
6319	NM_001022.3(RPS19):c.[43G>T;164C>T]		Pathogenic	no assertion criteria provided
579583	NM_000969.5(RPL5):c.169_172del (p.Asn57fs)	DIPK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1300197	NM_182922.4(HEATR3):c.400T>C (p.Cys134Arg)	HEATR3	Pathogenic	no assertion criteria provided
1334102	NM_182922.4(HEATR3):c.399+1G>T	HEATR3	Pathogenic	criteria provided, single submitter
1334103	NM_182922.4(HEATR3):c.719C>T (p.Pro240Leu)	HEATR3	Pathogenic	criteria provided, single submitter
1323536	NM_001022.4(RPS19):c.403_404del (p.Ala135fs)	RPS19	Pathogenic	criteria provided, single submitter
1338641	NM_001022.4(RPS19):c.302G>A (p.Arg101His)	RPS19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687347	NM_001022.4(RPS19):c.296_297del (p.Val99fs)	RPS19	Pathogenic	criteria provided, single submitter
1735592	NM_001022.4(RPS19):c.385dup (p.Arg129fs)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
1761564	NM_001022.4(RPS19):c.79A>T (p.Lys27Ter)	RPS19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138299	NM_001022.4(RPS19):c.94G>T (p.Glu32Ter)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
2412767	NM_001022.4(RPS19):c.316del (p.Ala106fs)	RPS19	Pathogenic	criteria provided, single submitter
2690490	NM_001022.4(RPS19):c.376C>T (p.Gln126Ter)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
2780440	NM_001022.4(RPS19):c.412-2A>G	RPS19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255048	NM_001022.4(RPS19):c.24_31dup (p.Gln11delinsProTer)	RPS19	Pathogenic	criteria provided, single submitter
3358916	NM_001022.4(RPS19):c.48_49del (p.Arg16fs)	RPS19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372494	NM_001022.4(RPS19):c.3G>T (p.Met1Ile)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
3766828	NM_001022.4(RPS19):c.1-2A>C	RPS19	Pathogenic	criteria provided, single submitter
587695	NM_001022.4(RPS19):c.367_368dup (p.Leu123_Thr124insTer)	RPS19	Pathogenic	no assertion criteria provided
6313	NM_001022.4(RPS19):c.280C>T (p.Arg94Ter)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
6314	NM_001022.4(RPS19):c.184C>T (p.Arg62Trp)	RPS19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6315	NM_001022.4(RPS19):c.98G>A (p.Trp33Ter)	RPS19	Pathogenic	criteria provided, multiple submitters, no conflicts
6316	NM_001022.4(RPS19):c.250A>T (p.Arg84Ter)	RPS19	Pathogenic	no assertion criteria provided
6317	NM_001022.4(RPS19):c.307del (p.Val103fs)	RPS19	Pathogenic	no assertion criteria provided
88978	NM_001022.3(RPS19):c.1-231_173-3418del	RPS19	Pathogenic	no assertion criteria provided
977494	NM_001022.4(RPS19):c.295_296delinsCAGCCGA (p.Val99fs)	RPS19	Pathogenic	criteria provided, single submitter
3236681	NM_001022.4(RPS19):c.353A>G (p.Asp118Gly)	MIR6797	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444176	NM_001022.4(RPS19):c.71del (p.Lys24fs)	RPS19	Likely pathogenic	criteria provided, single submitter
3234977	NM_001022.4(RPS19):c.14del (p.Thr5fs)	RPS19	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
RPS19	Definitive	Autosomal dominant	Diamond-Blackfan anemia 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPS19	Orphanet:124	Diamond-Blackfan anemia
RPL5	Orphanet:124	Diamond-Blackfan anemia
HEATR3	Orphanet:124	Diamond-Blackfan anemia

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS19	HGNC:10402	ENSG00000105372	P39019	Small ribosomal subunit protein eS19	gencc,clinvar
RPL5	HGNC:10360	ENSG00000122406	P46777	Large ribosomal subunit protein uL18	clinvar
HEATR3	HGNC:26087	ENSG00000155393	Q7Z4Q2	HEAT repeat-containing protein 3	clinvar
DIPK1A	HGNC:32213	ENSG00000154511	Q5T7M9	Divergent protein kinase domain 1A	clinvar
MIR6797	HGNC:50169	ENSG00000276926		microRNA 6797	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPS19	Small ribosomal subunit protein eS19	Component of the small ribosomal subunit.
RPL5	Large ribosomal subunit protein uL18	Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
HEATR3	HEAT repeat-containing protein 3	Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Kinase	1	5.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS19	Other/Unknown	no		Ribosomal_eS19, Ribosomal_eS19_CS, WH-like_DNA-bd_sf
RPL5	Other/Unknown	no		Rbsml_uL18_euk_arc, Ribosomal_uL18_C_euk, Ribosomal_L18
HEATR3	Other/Unknown	no		ARM-like, ARM-type_fold, SYO1-like
DIPK1A	Kinase	yes		FAM69_kinase_dom, FAM69_N
MIR6797	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
right uterine tube	1
skin of hip	1
upper leg skin	1
germinal epithelium of ovary	1
parietal pleura	1
leukocyte	1
monocyte	1
mononuclear cell	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
adrenal tissue	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS19	301	ubiquitous	marker	upper leg skin, right uterine tube, skin of hip
RPL5	292	ubiquitous	marker	germinal epithelium of ovary, primordial germ cell in gonad, parietal pleura
HEATR3	248	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
DIPK1A	275	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
MIR6797	108		yes	sural nerve, primordial germ cell in gonad, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL5	6,028
RPS19	5,129
HEATR3	2,193
DIPK1A	575
MIR6797	0

Intra-cohort edges

A	B	Sources
DIPK1A	RPL5	string_interaction
HEATR3	RPL5	string_interaction
RPL5	RPS19	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPS19	P39019	210
RPL5	P46777	184

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DIPK1A	Q5T7M9	83.20
HEATR3	Q7Z4Q2	83.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 51. Enrichment computed across 5 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
Peptide chain elongation	2	126.9×	4e-04	RPS19, RPL5
Viral mRNA Translation	2	126.9×	4e-04	RPS19, RPL5
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	2	125.5×	4e-04	RPS19, RPL5
Selenocysteine synthesis	2	120.2×	4e-04	RPS19, RPL5
Eukaryotic Translation Termination	2	120.2×	4e-04	RPS19, RPL5
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	2	117.7×	4e-04	RPS19, RPL5
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	2	117.7×	4e-04	RPS19, RPL5
Formation of a pool of free 40S subunits	2	112.0×	4e-04	RPS19, RPL5
Response of EIF2AK4 (GCN2) to amino acid deficiency	2	110.9×	4e-04	RPS19, RPL5
L13a-mediated translational silencing of Ceruloplasmin expression	2	101.1×	4e-04	RPS19, RPL5
SRP-dependent cotranslational protein targeting to membrane	2	100.2×	4e-04	RPS19, RPL5
GTP hydrolysis and joining of the 60S ribosomal subunit	2	100.2×	4e-04	RPS19, RPL5
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	2	97.6×	4e-04	RPS19, RPL5
Regulation of expression of SLITs and ROBOs	2	69.2×	8e-04	RPS19, RPL5
Major pathway of rRNA processing in the nucleolus and cytosol	2	61.7×	9e-04	RPS19, RPL5
Eukaryotic Translation Initiation	1	154.3×	0.018	RPS19
Cap-dependent Translation Initiation	1	154.3×	0.018	RPS19
SARS-CoV-1 modulates host translation machinery	1	154.3×	0.018	RPS19
Eukaryotic Translation Elongation	1	139.3×	0.019	RPS19
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1	135.9×	0.019	RPS19
Nonsense-Mediated Decay (NMD)	1	116.5×	0.020	RPS19
SARS-CoV-2 modulates host translation machinery	1	112.0×	0.020	RPS19
Influenza Viral RNA Transcription and Replication	1	107.7×	0.020	RPS19
Formation of the ternary complex, and subsequently, the 43S complex	1	107.7×	0.020	RPS19
Selenoamino acid metabolism	1	98.5×	0.020	RPS19
Translation initiation complex formation	1	95.2×	0.020	RPS19
Ribosomal scanning and start codon recognition	1	95.2×	0.020	RPS19
Influenza Infection	1	87.8×	0.020	RPS19
SARS-CoV-1-host interactions	1	87.8×	0.020	RPS19
Cellular response to starvation	1	82.8×	0.020	RPS19

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ribosomal large subunit biogenesis	2	295.6×	3e-04	RPL5, HEATR3
cytoplasmic translation	2	123.5×	9e-04	RPS19, RPL5
rRNA processing	2	94.4×	0.001	RPS19, RPL5
translation	2	68.5×	0.002	RPS19, RPL5
positive regulation of respiratory burst involved in inflammatory response	1	2808.7×	0.002	RPS19
nucleolus organization	1	1123.5×	0.003	RPS19
negative regulation of respiratory burst involved in inflammatory response	1	1123.5×	0.003	RPS19
ribosomal large subunit assembly	1	468.1×	0.005	RPL5
ribosomal small subunit assembly	1	468.1×	0.005	RPS19
erythrocyte maturation	1	280.9×	0.007	HEATR3
negative regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.007	RPL5
maturation of SSU-rRNA	1	255.3×	0.007	RPS19
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	224.7×	0.008	RPS19
monocyte chemotaxis	1	193.7×	0.008	RPS19
regulation of signal transduction by p53 class mediator	1	127.7×	0.011	RPL5
killing of cells of another organism	1	90.6×	0.014	RPS19
erythrocyte differentiation	1	89.2×	0.014	RPS19
ribosomal small subunit biogenesis	1	75.9×	0.015	RPS19
positive regulation of translation	1	75.9×	0.015	RPL5
defense response to Gram-negative bacterium	1	56.2×	0.019	RPS19
antimicrobial humoral immune response mediated by antimicrobial peptide	1	54.0×	0.019	RPS19
protein import into nucleus	1	48.0×	0.021	HEATR3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
RPS19	GENTAMICIN SULFATE
RPL5	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPS19	2	4
RPL5	1	4
HEATR3	0	0
DIPK1A	0	0
MIR6797	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPL5, RPS19
MOLIBRESIB	2	RPS19

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RPS19	97	Binding:97
RPL5	90	Binding:90

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
GENTAMICIN SULFATE	4	RPL5, RPS19
MOLIBRESIB	2	RPS19

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RPS19, RPL5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	DIPK1A
E	Difficult family or no structure, no drug	2	HEATR3, MIR6797

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HEATR3	0	RPL5
DIPK1A	0	—
MIR6797	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01362595	PHASE1/PHASE2	COMPLETED	Pilot Phase I/II Study of Amino Acid Leucine in Treatment of Patients With Transfusion-Dependent Diamond Blackfan Anemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEUCINE	3	1