Primary ciliary dyskinesia 28

Summary

Primary ciliary dyskinesia 28 (MONDO:0014216) is a disease caused by SPAG1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SPAG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 449

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	primary ciliary dyskinesia 28
Mondo ID	MONDO:0014216
OMIM	615505
DOID	DOID:0110607
UMLS	C3809706
MedGen	816036
GARD	0015977
Is cancer (heuristic)	no

Also known as: CILD28 · ciliary dyskinesia, primary, 28 · ciliary dyskinesia, primary, type 28 · primary ciliary dyskinesia caused by mutation in SPAG1 · primary ciliary dyskinesia type 28 · SPAG1 primary ciliary dyskinesia

Data availability: 449 ClinVar variants · 3 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 28

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 29, primary ciliary dyskinesia 30, primary ciliary dyskinesia 32, primary ciliary dyskinesia 33, 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

449 retrieved; paginated sample, class counts are floors:

174 likely benign, 157 uncertain significance, 52 pathogenic, 24 benign, 19 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4820075	NC_000008.11:g.101163836_101175815del	LOC113783879	Pathogenic	criteria provided, single submitter
1768804	NM_003114.5(SPAG1):c.1285_1294del (p.Gly429fs)	LOC130000832	Pathogenic	criteria provided, multiple submitters, no conflicts
2137068	NM_003114.5(SPAG1):c.1282_1294dup (p.Ala432fs)	LOC130000832	Pathogenic	criteria provided, single submitter
2917501	NM_003114.5(SPAG1):c.1244_1253del (p.Asp415fs)	LOC130000832	Pathogenic	criteria provided, single submitter
848747	NM_003114.5(SPAG1):c.1282_1294del (p.Ala428fs)	LOC130000832	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88681	NC_000008.11:g.100151617_100163589del	POLR2K	Pathogenic	no assertion criteria provided
1070816	NM_003114.5(SPAG1):c.557del (p.Ser186fs)	SPAG1	Pathogenic	criteria provided, single submitter
1076825	NM_003114.5(SPAG1):c.2200_2203del (p.Val734fs)	SPAG1	Pathogenic	criteria provided, single submitter
1188647	NM_003114.5(SPAG1):c.2089C>T (p.Arg697Ter)	SPAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323639	NM_003114.5(SPAG1):c.1113_1149del (p.Gly372fs)	SPAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323640	NM_003114.5(SPAG1):c.1119del (p.Ala374fs)	SPAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1408626	NM_003114.5(SPAG1):c.1012del (p.Arg338fs)	SPAG1	Pathogenic	criteria provided, single submitter
1442364	NM_003114.5(SPAG1):c.2136_2139del (p.Asp713fs)	SPAG1	Pathogenic	criteria provided, single submitter
1451939	NM_003114.5(SPAG1):c.1785G>A (p.Trp595Ter)	SPAG1	Pathogenic	criteria provided, single submitter
1458709	NC_000008.10:g.(?101174509)(101174668_?)del	SPAG1	Pathogenic	criteria provided, single submitter
1929731	NM_003114.5(SPAG1):c.324dup (p.Glu109fs)	SPAG1	Pathogenic	criteria provided, single submitter
1956907	NM_003114.5(SPAG1):c.2577del (p.Asn859fs)	SPAG1	Pathogenic	criteria provided, single submitter
1992486	NM_003114.5(SPAG1):c.1584_1606del (p.Met529fs)	SPAG1	Pathogenic	criteria provided, single submitter
2014694	NM_003114.5(SPAG1):c.1024C>T (p.Gln342Ter)	SPAG1	Pathogenic	criteria provided, single submitter
2102695	NM_003114.5(SPAG1):c.237dup (p.Pro80fs)	SPAG1	Pathogenic	criteria provided, single submitter
2179139	NM_003114.5(SPAG1):c.1097-11C>G	SPAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2791927	NM_003114.5(SPAG1):c.595+1G>A	SPAG1	Pathogenic	criteria provided, single submitter
2915487	NM_003114.5(SPAG1):c.2367del (p.Ser789fs)	SPAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2954763	NM_003114.5(SPAG1):c.1687_1688del (p.Arg563fs)	SPAG1	Pathogenic	criteria provided, single submitter
3245529	NC_000008.10:g.(?101251448)(101253250_?)del	SPAG1	Pathogenic	criteria provided, single submitter
3245531	NC_000008.10:g.(?101194532)(101196884_?)del	SPAG1	Pathogenic	criteria provided, single submitter
3619652	NM_003114.5(SPAG1):c.1111_1120dup (p.Ala374fs)	SPAG1	Pathogenic	criteria provided, single submitter
3667593	NM_003114.5(SPAG1):c.2217_2218insAA (p.Leu740fs)	SPAG1	Pathogenic	criteria provided, single submitter
3693125	NM_003114.5(SPAG1):c.172dup (p.Thr58fs)	SPAG1	Pathogenic	criteria provided, single submitter
3705933	NM_003114.5(SPAG1):c.305G>A (p.Trp102Ter)	SPAG1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SPAG1	Definitive	Autosomal recessive	primary ciliary dyskinesia 28	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPAG1	Orphanet:244	Primary ciliary dyskinesia

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
SPAG1	HGNC:11212	ENSG00000104450	Q07617	Sperm-associated antigen 1	gencc,clinvar
POLR2K	HGNC:9198	ENSG00000147669	P53803	DNA-directed RNA polymerases I, II, and III subunit RPABC4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPAG1	Sperm-associated antigen 1	May play a role in the cytoplasmic assembly of the ciliary dynein arms.
POLR2K	DNA-directed RNA polymerases I, II, and III subunit RPABC4	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA 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)
SPAG1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, RPAP3-like_C
POLR2K	Other/Unknown	no		RNAP_P/RPABC4, RPABC4/Spt4, RPABC4

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
bronchial epithelial cell	1
mucosa of sigmoid colon	1
palpebral conjunctiva	1
calcaneal tendon	1
islet of Langerhans	1
popliteal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPAG1	249	ubiquitous	marker	bronchial epithelial cell, mucosa of sigmoid colon, palpebral conjunctiva
POLR2K	295	ubiquitous	marker	islet of Langerhans, calcaneal tendon, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR2K	2,950
SPAG1	2,175

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2K	P53803	57
SPAG1	Q07617	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR2 mutant receptor activation	1	761.3×	0.008	POLR2K
RNA Polymerase III Chain Elongation	1	634.4×	0.008	POLR2K
Signaling by FGFR2 IIIa TM	1	601.0×	0.008	POLR2K
Abortive elongation of HIV-1 transcript in the absence of Tat	1	496.5×	0.008	POLR2K
RNA Polymerase III Transcription Termination	1	496.5×	0.008	POLR2K
MicroRNA (miRNA) biogenesis	1	456.8×	0.008	POLR2K
Activation of HOX genes during differentiation	1	439.2×	0.008	POLR2K
Signaling by FGFR in disease	1	423.0×	0.008	POLR2K
FGFR2 alternative splicing	1	423.0×	0.008	POLR2K
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	423.0×	0.008	POLR2K
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	407.9×	0.008	POLR2K
Signaling by FGFR2	1	407.9×	0.008	POLR2K
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	407.9×	0.008	POLR2K
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	407.9×	0.008	POLR2K
RNA Pol II CTD phosphorylation and interaction with CE	1	407.9×	0.008	POLR2K
PIWI-interacting RNA (piRNA) biogenesis	1	393.8×	0.008	POLR2K
mRNA Capping	1	380.7×	0.008	POLR2K
Telomere Maintenance	1	368.4×	0.008	POLR2K
Pausing and recovery of Tat-mediated HIV elongation	1	368.4×	0.008	POLR2K
Tat-mediated HIV elongation arrest and recovery	1	368.4×	0.008	POLR2K
Gene Silencing by RNA	1	356.9×	0.008	POLR2K
HIV elongation arrest and recovery	1	346.1×	0.008	POLR2K
Pausing and recovery of HIV elongation	1	346.1×	0.008	POLR2K
Signaling by FGFR	1	346.1×	0.008	POLR2K
Positive epigenetic regulation of rRNA expression	1	346.1×	0.008	POLR2K
Formation of the Early Elongation Complex	1	335.9×	0.008	POLR2K
Formation of the HIV-1 Early Elongation Complex	1	335.9×	0.008	POLR2K
HIV Transcription Elongation	1	335.9×	0.008	POLR2K
RNA Polymerase III Transcription Initiation	1	335.9×	0.008	POLR2K
RNA Polymerase I Transcription Termination	1	326.3×	0.008	POLR2K

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
regulation of transcription by RNA polymerase I	1	2106.5×	0.003	POLR2K
axonemal dynein complex assembly	1	526.6×	0.005	SPAG1
transcription by RNA polymerase III	1	383.0×	0.005	POLR2K
single fertilization	1	91.6×	0.016	SPAG1
transcription by RNA polymerase II	1	35.3×	0.030	POLR2K
protein stabilization	1	33.4×	0.030	SPAG1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPAG1	0	0
POLR2K	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SPAG1, POLR2K

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)
SPAG1	0	—
POLR2K	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.