Primary ciliary dyskinesia 33

Summary

Primary ciliary dyskinesia 33 (MONDO:0014750) is a disease caused by DRC4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: DRC4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 358

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	primary ciliary dyskinesia 33
Mondo ID	MONDO:0014750
OMIM	616726
DOID	DOID:0110619
UMLS	C4225230
MedGen	898734
GARD	0016154
Is cancer (heuristic)	no

Also known as: CILD33 · ciliary dyskinesia, primary, 33 · ciliary dyskinesia, primary, type 33 · GAS8 primary ciliary dyskinesia · primary ciliary dyskinesia caused by mutation in GAS8 · primary ciliary dyskinesia type 33

Data availability: 358 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › primary ciliary dyskinesia › primary ciliary dyskinesia 33

Related subtypes (58): ciliary discoordination due to random ciliary orientation, ciliary dyskinesia with transposition of ciliary microtubules, ciliary dyskinesia with defective radial spokes, ciliary dyskinesia with excessively long cilia, Stromme syndrome, primary ciliary dyskinesia 1, ciliary dyskinesia, primary, 36, X-linked, primary ciliary dyskinesia 2, primary ciliary dyskinesia 3, primary ciliary dyskinesia 4, primary ciliary dyskinesia 5, primary ciliary dyskinesia 6, primary ciliary dyskinesia 7, primary ciliary dyskinesia 8, primary ciliary dyskinesia 9, primary ciliary dyskinesia 10, primary ciliary dyskinesia 11, primary ciliary dyskinesia 12, primary ciliary dyskinesia 13, primary ciliary dyskinesia 14, primary ciliary dyskinesia 15, primary ciliary dyskinesia 16, primary ciliary dyskinesia 17, primary ciliary dyskinesia 18, primary ciliary dyskinesia 19, primary ciliary dyskinesia 20, primary ciliary dyskinesia 21, primary ciliary dyskinesia 22, primary ciliary dyskinesia 23, primary ciliary dyskinesia 24, primary ciliary dyskinesia 25, primary ciliary dyskinesia 26, primary ciliary dyskinesia 27, primary ciliary dyskinesia 28, primary ciliary dyskinesia 29, primary ciliary dyskinesia 30, primary ciliary dyskinesia 32, primary ciliary dyskinesia 34, primary ciliary dyskinesia 35, ciliary dyskinesia, primary, 46, ciliary dyskinesia, primary, 47, and lissencephaly, ciliary dyskinesia, primary, 48, without situs inversus, ciliary dyskinesia, primary, 39, ciliary dyskinesia, primary, 40, ciliary dyskinesia, primary, 41, ciliary dyskinesia, primary, 42, ciliary dyskinesia, primary, 43, ciliary dyskinesia, primary, 44, ciliary dyskinesia, primary, 45, ciliary dyskinesia, primary, 37, ciliary dyskinesia, primary, 38, ciliary dyskinesia, primary, 54, ciliary dyskinesia, primary, 49, without situs inversus, ciliary dyskinesia, primary, 50, ciliary dyskinesia, primary, 51, ciliary dyskinesia, primary, 52, ciliary dyskinesia, primary, 53, CFAP46-related primary ciliary dyskinesia

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

358 retrieved; paginated sample, class counts are floors:

162 likely benign, 140 uncertain significance, 20 benign, 17 pathogenic, 8 likely pathogenic, 8 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076474	NM_001481.3(DRC4):c.886C>T (p.Gln296Ter)	DRC4	Pathogenic	criteria provided, single submitter
219123	NM_001481.3(DRC4):c.1000C>T (p.Arg334Ter)	DRC4	Pathogenic	criteria provided, single submitter
219124	NM_001481.3(DRC4):c.1069C>T (p.Gln357Ter)	DRC4	Pathogenic	criteria provided, multiple submitters, no conflicts
2201812	NM_001481.3(DRC4):c.887del (p.Gln296fs)	DRC4	Pathogenic	criteria provided, single submitter
2663811	NM_001481.3(DRC4):c.189G>A (p.Trp63Ter)	DRC4	Pathogenic	criteria provided, single submitter
2898953	NM_001481.3(DRC4):c.97G>T (p.Glu33Ter)	DRC4	Pathogenic	criteria provided, single submitter
3243533	NC_000016.9:g.(?90089130)(90109753_?)del	DRC4	Pathogenic	criteria provided, single submitter
3610990	NM_001481.3(DRC4):c.796G>T (p.Glu266Ter)	DRC4	Pathogenic	criteria provided, single submitter
3639758	NM_001481.3(DRC4):c.1105_1106insTA (p.Arg369fs)	DRC4	Pathogenic	criteria provided, single submitter
3679698	NM_001481.3(DRC4):c.278_279dup (p.Glu94fs)	DRC4	Pathogenic	criteria provided, single submitter
475553	NC_000016.10:g.(?90022702)(90040529_?)del	DRC4	Pathogenic	criteria provided, single submitter
4783817	NM_001481.3(DRC4):c.547C>T (p.Arg183Ter)	DRC4	Pathogenic	criteria provided, single submitter
4792002	NM_001481.3(DRC4):c.145C>T (p.Arg49Ter)	DRC4	Pathogenic	criteria provided, single submitter
955888	NM_001481.3(DRC4):c.718dup (p.Ile240fs)	DRC4	Pathogenic	criteria provided, single submitter
1455472	NC_000016.9:g.(?90089130)(90094150_?)del	GAS8	Pathogenic	criteria provided, single submitter
219122	NM_001481.3(GAS8):c.927C>A (p.Cys309Ter)	GAS8	Pathogenic	no assertion criteria provided
2424183	NC_000016.9:g.(?90089130)(90089152_?)del	GAS8	Pathogenic	criteria provided, single submitter
1065987	NM_001481.3(DRC4):c.1011+2T>C	DRC4	Likely pathogenic	criteria provided, single submitter
2431345	NM_001481.3(DRC4):c.495+1G>T	DRC4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3001041	NM_001481.3(DRC4):c.757-1G>C	DRC4	Likely pathogenic	criteria provided, single submitter
3719545	NM_001481.3(DRC4):c.1221+1G>T	DRC4	Likely pathogenic	criteria provided, single submitter
4502245	NM_001481.3(DRC4):c.495+1G>A	DRC4	Likely pathogenic	criteria provided, single submitter
4782919	NM_001481.3(DRC4):c.1011+1G>T	DRC4	Likely pathogenic	criteria provided, single submitter
4791533	NM_001481.3(DRC4):c.924+2_924+3del	DRC4	Likely pathogenic	criteria provided, single submitter
804479	NM_001481.3(GAS8):c.865del (p.Glu289fs)	GAS8	Likely pathogenic	criteria provided, single submitter
1497944	NM_001481.3(DRC4):c.649G>A (p.Gly217Ser)	DRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2048643	NM_001481.3(DRC4):c.1354G>A (p.Val452Met)	DRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475568	NM_001481.3(DRC4):c.808G>C (p.Ala270Pro)	DRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542268	NM_001481.3(DRC4):c.316C>G (p.Leu106Val)	DRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542273	NM_001481.3(DRC4):c.841G>C (p.Asp281His)	DRC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
DRC4	Definitive	Autosomal recessive	primary ciliary dyskinesia 33	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DRC4	Orphanet:244	Primary ciliary dyskinesia
ACSF3	Orphanet:289504	Combined malonic and methylmalonic acidemia

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
DRC4	HGNC:4166	ENSG00000141013	O95995	Dynein regulatory complex subunit 4	gencc,clinvar
ACSF3	HGNC:27288	ENSG00000176715	Q4G176	Malonate–CoA ligase ACSF3, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DRC4	Dynein regulatory complex subunit 4	Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.
ACSF3	Malonate–CoA ligase ACSF3, mitochondrial	Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester.

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)
DRC4	Other/Unknown	no		GAS8_dom, GAS8
ACSF3	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C

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
right uterine tube	1
sural nerve	1
type B pancreatic cell	1
granulocyte	1
mucosa of transverse colon	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DRC4	261	ubiquitous	marker	right uterine tube, sural nerve, type B pancreatic cell
ACSF3	173	ubiquitous	marker	mucosa of transverse colon, granulocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSF3	2,854
DRC4	1,532

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DRC4	O95995	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSF3	Q4G176	86.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Activation of SMO	1	317.2×	0.009	DRC4
Synthesis of very long-chain fatty acyl-CoAs	1	228.4×	0.009	ACSF3
Fatty acyl-CoA biosynthesis	1	219.6×	0.009	ACSF3
Fatty acid metabolism	1	65.6×	0.023	ACSF3
Metabolism of lipids	1	15.8×	0.075	ACSF3
Metabolism	1	5.8×	0.165	ACSF3

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
malonate catabolic process	1	8426.0×	0.002	ACSF3
positive regulation of protein localization to cilium	1	1404.3×	0.006	DRC4
long-chain fatty-acyl-CoA biosynthetic process	1	421.3×	0.009	ACSF3
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.009	DRC4
cilium movement involved in cell motility	1	337.0×	0.009	DRC4
cilium organization	1	300.9×	0.009	DRC4
axoneme assembly	1	271.8×	0.009	DRC4
positive regulation of smoothened signaling pathway	1	210.7×	0.010	DRC4
protein localization to cilium	1	200.6×	0.010	DRC4
fatty acid biosynthetic process	1	175.5×	0.010	ACSF3
determination of left/right symmetry	1	127.7×	0.013	DRC4
fatty acid metabolic process	1	96.8×	0.015	ACSF3
establishment of localization in cell	1	80.2×	0.017	DRC4
microtubule cytoskeleton organization	1	60.6×	0.020	DRC4
flagellated sperm motility	1	58.5×	0.020	DRC4
protein-containing complex assembly	1	56.9×	0.020	DRC4
brain development	1	39.8×	0.026	DRC4
negative regulation of cell population proliferation	1	21.1×	0.047	DRC4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DRC4	0	0
ACSF3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACSF3	1	Binding:1

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DRC4, ACSF3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DRC4	0	—
ACSF3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.