SPAG1

Summary

SPAG1 (sperm associated antigen 1, HGNC:11212) is a protein-coding gene on chromosome 8q22.2, encoding Sperm-associated antigen 1 (Q07617). May play a role in the cytoplasmic assembly of the ciliary dynein arms.

The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein expressed by this gene is recognized by anti-sperm agglutinating antibodies from an infertile woman. Furthermore, immunization of female rats with the recombinant human protein reduced fertility. This protein localizes to the plasma membrane of germ cells in the testis and to the post-acrosomal plasma membrane of mature spermatozoa. Recombinant polypeptide binds GTP and exhibits GTPase activity. Thus, this protein may regulate GTP signal transduction pathways involved in spermatogenesis and fertilization. Two transcript variants of this gene encode the same protein.

Source: NCBI Gene 6674 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ciliary dyskinesia 28 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 545 total — 51 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 56
• MANE Select transcript: NM_003114

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11212
Approved symbol	SPAG1
Name	sperm associated antigen 1
Location	8q22.2
Locus type	gene with protein product
Status	Approved
Aliases	SP75, FLJ32920, HSD-3.8, TPIS, CT140, CILD28, DNAAF13
Ensembl gene	ENSG00000104450
Ensembl biotype	protein_coding
OMIM	603395
Entrez	6674

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000251809, ENST00000388798, ENST00000519409, ENST00000519424, ENST00000520508, ENST00000520643, ENST00000523302, ENST00000936429, ENST00000964470, ENST00000964471, ENST00000964472

RefSeq mRNA: 3 — MANE Select: NM_003114 NM_001374321, NM_003114, NM_172218

CCDS: CCDS34930

Canonical transcript exons

ENST00000388798 — 19 exons

Exon	Start	End
ENSE00000981004	100240403	100240771
ENSE00000981005	100240891	100241904
ENSE00001026908	100194112	100194268
ENSE00001026912	100183375	100183436
ENSE00001026915	100187120	100187250
ENSE00001026917	100183956	100184062
ENSE00001026919	100191390	100191496
ENSE00001026920	100184628	100184733
ENSE00001026923	100177816	100177941
ENSE00001088687	100165814	100165973
ENSE00001165555	100220279	100220431
ENSE00001250023	100162279	100162420
ENSE00001503990	100233411	100233537
ENSE00001503991	100231156	100231288
ENSE00001503992	100213819	100213918
ENSE00001503993	100213090	100213428
ENSE00001523457	100158587	100158616
ENSE00003589555	100239240	100239404
ENSE00003656084	100225173	100225339

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 96.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.2733 / max 151.8577, expressed in 1488 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89970	2.6158	1070
89968	1.8826	684
89967	1.0081	524
89971	0.6631	272
205273	0.0737	18
89969	0.0300	12

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	96.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.15	gold quality
palpebral conjunctiva	UBERON:0001812	91.47	gold quality
colonic mucosa	UBERON:0000317	91.24	gold quality
epithelium of bronchus	UBERON:0002031	91.15	gold quality
bronchus	UBERON:0002185	90.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.43	gold quality
rectum	UBERON:0001052	89.38	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.02	gold quality
lower esophagus mucosa	UBERON:0035834	88.53	gold quality
right uterine tube	UBERON:0001302	88.05	gold quality
colonic epithelium	UBERON:0000397	87.55	gold quality
upper leg skin	UBERON:0004262	85.88	gold quality
oral cavity	UBERON:0000167	85.87	gold quality
nasal cavity mucosa	UBERON:0001826	85.83	gold quality
epithelium of nasopharynx	UBERON:0001951	85.50	gold quality
nasal cavity epithelium	UBERON:0005384	85.16	gold quality
mucosa of transverse colon	UBERON:0004991	85.01	gold quality
amniotic fluid	UBERON:0000173	84.38	gold quality
secondary oocyte	CL:0000655	82.78	gold quality
calcaneal tendon	UBERON:0003701	82.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.40	gold quality
esophagus squamous epithelium	UBERON:0006920	81.98	gold quality
choroid plexus epithelium	UBERON:0003911	81.32	gold quality
transverse colon	UBERON:0001157	80.93	gold quality
islet of Langerhans	UBERON:0000006	80.12	gold quality
esophagus mucosa	UBERON:0002469	79.68	gold quality
epithelium of esophagus	UBERON:0001976	79.61	gold quality
skin of leg	UBERON:0001511	79.55	gold quality
left testis	UBERON:0004533	79.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	10.70
E-ANND-3	yes	9.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting SPAG1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-12124	99.68	69.17	2700

Literature-anchored findings (GeneRIF, showing 10)

• The h-Sp-1 molecule is expressed in sperm and testes and plays a role in fertilization. (PMID:12846798)
• HSD-3.8 (SPAG1), interacts with G-protein beta 1 subunit and activates extracellular signal-regulated kinases 1 and 2 (PMID:16368546)
• Immunocytochemical analysis demonstrated colocalization of SPAG1 with microtubules, and their association was confirmed by co-immunoprecipitation; subsequent motility assays further substantiated a potential role of SPAG1 in cancer cell motility (PMID:16983343)
• SPAG1 probably plays a role in the cytoplasmic assembly. (PMID:24055112)
• Demonstrated that a SPAG1 sub-fragment, containing a putative P-loop motif, cannot efficiently bind and hydrolyze GTP in vitro Our data challenge the interpretation of SPAG1 possessing GTPase activity. We propose instead that SPAG1 regulates nucleotide hydrolysis activity of the HSP and RUVBL1/2 partners. (PMID:31118266)
• Bioinformatics analysis of the genes involved in the extension of prostate cancer to adjacent lymph nodes by supervised and unsupervised machine learning methods: The role of SPAG1 and PLEKHF2. (PMID:32619574)
• Optimizing the First TPR Domain of the Human SPAG1 Protein Provides Insight into the HSP70 and HSP90 Binding Properties. (PMID:33739091)
• The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia. (PMID:35178554)
• Comprehensive analysis of SPAG1 expression as a prognostic and predictive biomarker in acute myeloid leukemia by integrative bioinformatics and clinical validation. (PMID:35227274)
• SPAG1 promotes the development of AML by activating the ERK/MAPK signaling pathway and affects the chemotherapy sensitivity of venetoclax. (PMID:35951456)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	spag1a	ENSDARG00000004017
danio_rerio	spag1b	ENSDARG00000069499
mus_musculus	Spag1	ENSMUSG00000037617
rattus_norvegicus	Spag1	ENSRNOG00000010078

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), STUB1 (ENSG00000103266), SGTA (ENSG00000104969), TTC1 (ENSG00000113312), TTC31 (ENSG00000115282), UNC45A (ENSG00000140553), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), TOMM70 (ENSG00000154174), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725), DNAAF4 (ENSG00000256061)

Protein

Protein identifiers

Sperm-associated antigen 1 — Q07617 (reviewed: Q07617)

Alternative names: HSD-3.8, Infertility-related sperm protein Spag-1

All UniProt accessions (1): Q07617

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the cytoplasmic assembly of the ciliary dynein arms. May play a role in fertilization. Binds GTP and has GTPase activity.

Subcellular location. Cytoplasm. Dynein axonemal particle.

Tissue specificity. Present in most tissues, including lung, with the strongest expression in brain, colon, kidney, and testis. In sperm and testis, detected in particular in pachytene primary spermatocytes. Up-regulated in pancreatic tumor tissues and not in normal pancreatic tissue.

Disease relevance. Ciliary dyskinesia, primary, 28 (CILD28) [MIM:615505] A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Antibodies against SPAG1 interfere with fertilization.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07617-1	1	yes
Q07617-2	2

RefSeq proteins (3): NP_001361250, NP_003105, NP_757367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR025986	RPAP3-like_C	Domain
IPR051982	CiliaryAsmbly_MitoImport	Family

Pfam: PF00515, PF13181, PF13877

UniProt features (44 total): helix 14, repeat 9, compositionally biased region 5, modified residue 4, sequence variant 3, sequence conflict 3, region of interest 2, splice variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9HB4	ELECTRON MICROSCOPY	3.56
6I57	SOLUTION NMR
7BEV	SOLUTION NMR
9HKR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07617-F1	74.50	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 781–788

Post-translational modifications (4): 347, 354, 423, 791

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 254 (showing top): GOBP_SINGLE_FERTILIZATION, ELVIDGE_HYPOXIA_DN, LU_IL4_SIGNALING, ONDER_CDH1_TARGETS_3_DN, GOBP_AXONEMAL_DYNEIN_COMPLEX_ASSEMBLY, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CILIUM_ORGANIZATION, GOBP_PROTEIN_STABILIZATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_ORGANELLE_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_STABILITY, NIKOLSKY_BREAST_CANCER_8Q12_Q22_AMPLICON, GOBP_MICROTUBULE_BUNDLE_FORMATION, chr8q22

GO Biological Process (3): single fertilization (GO:0007338), protein stabilization (GO:0050821), axonemal dynein complex assembly (GO:0070286)

GO Molecular Function (4): GTP binding (GO:0005525), hydrolase activity (GO:0016787), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), sperm principal piece (GO:0097228), protein folding chaperone complex (GO:0101031), dynein axonemal particle (GO:0120293)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
fertilization	1
regulation of protein stability	1
axoneme assembly	1
protein-containing complex assembly	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
sperm flagellum	1
intracellular protein-containing complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2097 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAG1	DNAAF6	Q9NQM4	857
SPAG1	PIH1D2	Q8WWB5	831
SPAG1	DNAAF5	Q86Y56	816
SPAG1	DNAAF3	Q8N9W5	809
SPAG1	DNAI2	Q9GZS0	806
SPAG1	DNAAF11	Q86X45	799
SPAG1	ZMYND10	O75800	795
SPAG1	DNAAF19	Q8IW40	780
SPAG1	CFAP298	P57076	773
SPAG1	PIH1D1	Q9NWS0	754
SPAG1	DNAAF1	Q8NEP3	750
SPAG1	RSPH4A	Q5TD94	738
SPAG1	RSPH9	Q9H1X1	733
SPAG1	RSPH1	Q8WYR4	723
SPAG1	RUVBL2	Q9Y230	717

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSP90AA1	USP19	psi-mi:“MI:0914”(association)	0.530
MAGEA1	MAGEB3	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
SPAG1	SSR3	psi-mi:“MI:0915”(physical association)	0.400
Cep152	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
Mis12		psi-mi:“MI:0914”(association)	0.350
Eef1a1	ERLIN2	psi-mi:“MI:0914”(association)	0.350
Cobll1	ABLIM1	psi-mi:“MI:0914”(association)	0.350
ATL3	SNX14	psi-mi:“MI:0914”(association)	0.350
Vps25	SPAG1	psi-mi:“MI:0914”(association)	0.350
LDHD	METTL8	psi-mi:“MI:0914”(association)	0.350
MAGEA1	ANKHD1	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
S100A6	VWA8	psi-mi:“MI:0914”(association)	0.350
HSPA2	HGS	psi-mi:“MI:0914”(association)	0.350
RDX	RNF113A	psi-mi:“MI:0914”(association)	0.350
WDR72	DNAJB5	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
BBX	SPAG1	psi-mi:“MI:0915”(physical association)	0.000
SPAG1	NOPCHAP1	psi-mi:“MI:0915”(physical association)	0.000
SPAG1	PRPF38A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (54): SPAG1 (Affinity Capture-MS), SPAG1 (Biochemical Activity), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Proximity Label-MS), SPAG1 (Affinity Capture-MS), SPAG1 (Affinity Capture-MS), C12orf45 (Affinity Capture-MS), PRPF38A (Affinity Capture-MS), SPAG1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMA8, A1A5P5, A2A6Q5, A6QNM3, A7Z061, E7F187, E9Q6P5, F7BJB9, O13046, O76094, P09798, P10505, P17885, P30260, P33731, P38042, P41889, Q05B30, Q06AN9, Q07617, Q13099, Q13416, Q32NR4, Q32NU8, Q3UMY5, Q4R6M4, Q4V8A2, Q5R629, Q5RE52, Q5TYV4, Q5U245, Q5ZKQ3, Q61371, Q6NU95, Q6PA97, Q6XV80, Q7Z3E5, Q7ZUV2, Q86TV6, Q8BGB2

Diamond homologs: A4K2V0, A6HD62, A6ZRW3, D7REX8, F1RBN2, F4IRM4, F4JTI1, F4K487, F4KCL7, O13754, O14217, O16259, O35814, O48802, O54981, O94826, O95801, P07213, P23231, P25638, P31948, P33313, P38825, P53041, P53042, Q07617, Q12118, Q13451, Q15785, Q32PZ3, Q3KRD5, Q3ZBR5, Q43207, Q4R8N7, Q5EA11, Q5PPS5, Q5R8D8, Q5RAP0, Q5U2X2, Q5VJS5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SPAG1	“form complex”	“R2SP co-chaperone”	binding
PRKCA	unknown	SPAG1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

545 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	12
Uncertain significance	201
Likely benign	176
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070816	NM_003114.5(SPAG1):c.557del (p.Ser186fs)	Pathogenic
1076825	NM_003114.5(SPAG1):c.2200_2203del (p.Val734fs)	Pathogenic
1188647	NM_003114.5(SPAG1):c.2089C>T (p.Arg697Ter)	Pathogenic
1323638	NM_003114.5(SPAG1):c.742C>T (p.Arg248Ter)	Pathogenic
1323639	NM_003114.5(SPAG1):c.1113_1149del (p.Gly372fs)	Pathogenic
1323640	NM_003114.5(SPAG1):c.1119del (p.Ala374fs)	Pathogenic
1408626	NM_003114.5(SPAG1):c.1012del (p.Arg338fs)	Pathogenic
1442364	NM_003114.5(SPAG1):c.2136_2139del (p.Asp713fs)	Pathogenic
1451939	NM_003114.5(SPAG1):c.1785G>A (p.Trp595Ter)	Pathogenic
1458709	NC_000008.10:g.(?101174509)(101174668_?)del	Pathogenic
1929731	NM_003114.5(SPAG1):c.324dup (p.Glu109fs)	Pathogenic
1956907	NM_003114.5(SPAG1):c.2577del (p.Asn859fs)	Pathogenic
1992486	NM_003114.5(SPAG1):c.1584_1606del (p.Met529fs)	Pathogenic
2014694	NM_003114.5(SPAG1):c.1024C>T (p.Gln342Ter)	Pathogenic
2102695	NM_003114.5(SPAG1):c.237dup (p.Pro80fs)	Pathogenic
2179139	NM_003114.5(SPAG1):c.1097-11C>G	Pathogenic
2791927	NM_003114.5(SPAG1):c.595+1G>A	Pathogenic
2954763	NM_003114.5(SPAG1):c.1687_1688del (p.Arg563fs)	Pathogenic
3245529	NC_000008.10:g.(?101251448)(101253250_?)del	Pathogenic
3245531	NC_000008.10:g.(?101194532)(101196884_?)del	Pathogenic
3619652	NM_003114.5(SPAG1):c.1111_1120dup (p.Ala374fs)	Pathogenic
3667593	NM_003114.5(SPAG1):c.2217_2218insAA (p.Leu740fs)	Pathogenic
3693125	NM_003114.5(SPAG1):c.172dup (p.Thr58fs)	Pathogenic
3705933	NM_003114.5(SPAG1):c.305G>A (p.Trp102Ter)	Pathogenic
3960175	NM_003114.5(SPAG1):c.614del (p.Lys205fs)	Pathogenic
410980	NM_003114.5(SPAG1):c.319A>T (p.Lys107Ter)	Pathogenic
410993	NM_003114.5(SPAG1):c.1519dup (p.Ile507fs)	Pathogenic
411002	NM_003114.5(SPAG1):c.325_326del (p.Glu109fs)	Pathogenic
417543	NC_000008.11:g.(?100162279)(100162420_?)del	Pathogenic
4292000	NM_003114.5(SPAG1):c.2025del (p.Ala676fs)	Pathogenic

SpliceAI

3281 predictions. Top by Δscore:

Variant	Effect	Δscore
8:100158116:GCA:G	donor_gain	1.0000
8:100158119:G:GG	donor_gain	1.0000
8:100162278:GCT:G	acceptor_gain	1.0000
8:100162278:GCTAT:G	acceptor_gain	1.0000
8:100162421:G:GA	donor_loss	1.0000
8:100162422:T:A	donor_loss	1.0000
8:100165811:A:AG	acceptor_gain	1.0000
8:100165812:A:AG	acceptor_gain	1.0000
8:100165813:G:GG	acceptor_gain	1.0000
8:100165970:AAAG:A	donor_loss	1.0000
8:100165972:AG:A	donor_loss	1.0000
8:100165973:GG:G	donor_loss	1.0000
8:100165974:G:A	donor_loss	1.0000
8:100165975:T:A	donor_loss	1.0000
8:100177815:GA:G	acceptor_gain	1.0000
8:100177815:GAGT:G	acceptor_gain	1.0000
8:100177815:GAGTT:G	acceptor_gain	1.0000
8:100177938:CAAG:C	donor_loss	1.0000
8:100177939:AAG:A	donor_loss	1.0000
8:100177940:AGG:A	donor_loss	1.0000
8:100177941:GGTAG:G	donor_loss	1.0000
8:100177942:GTAGG:G	donor_loss	1.0000
8:100177943:T:A	donor_loss	1.0000
8:100183430:GGGA:G	donor_gain	1.0000
8:100183431:GGA:G	donor_gain	1.0000
8:100183433:A:AG	donor_gain	1.0000
8:100183437:G:GG	donor_gain	1.0000
8:100183950:T:G	acceptor_gain	1.0000
8:100183953:A:AG	acceptor_gain	1.0000
8:100183954:A:G	acceptor_gain	1.0000

AlphaMissense

6122 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:100220323:G:C	R527P	0.998
8:100191404:G:C	A283P	0.997
8:100183429:T:A	W161R	0.996
8:100183429:T:C	W161R	0.996
8:100187161:G:C	R248P	0.996
8:100187169:G:C	A251P	0.996
8:100191402:G:C	R282P	0.996
8:100220325:G:C	A528P	0.996
8:100233512:G:C	R697P	0.996
8:100184714:G:C	A228P	0.995
8:100233514:G:C	A698P	0.995
8:100187121:A:C	S235R	0.994
8:100187123:C:A	S235R	0.994
8:100187123:C:G	S235R	0.994
8:100187163:G:C	A249P	0.994
8:100220321:G:C	R526S	0.994
8:100220321:G:T	R526S	0.994
8:100233510:A:C	R696S	0.994
8:100233510:A:T	R696S	0.994
8:100191399:G:C	R281P	0.993
8:100213395:T:C	Y468H	0.993
8:100213863:G:C	A494P	0.993
8:100213913:T:G	C510W	0.993
8:100220326:C:A	A528E	0.993
8:100233448:G:C	A676P	0.993
8:100233509:G:C	R696T	0.993
8:100183431:G:C	W161C	0.992
8:100183431:G:T	W161C	0.992
8:100213871:T:G	C496W	0.992
8:100213911:T:C	C510R	0.992

dbSNP variants (sampled 300 via entrez): RS1000061461 (8:100164487 C>T), RS1000117443 (8:100157983 G>A), RS1000128311 (8:100233847 G>A), RS1000155403 (8:100163775 A>G), RS1000157513 (8:100194011 T>C,G), RS1000179833 (8:100199854 T>C), RS1000209355 (8:100194459 T>C), RS1000227162 (8:100230660 G>C), RS1000313196 (8:100205503 C>T), RS1000356457 (8:100227189 C>T), RS1000387488 (8:100227141 AATTTCGC>A), RS1000391141 (8:100234022 T>A), RS1000443509 (8:100233669 C>A,G), RS1000449926 (8:100190847 T>C), RS1000521510 (8:100186133 A>G)

Disease associations

OMIM: gene MIM:603395 | disease phenotypes: MIM:615505, MIM:244400, MIM:615005

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ciliary dyskinesia 28	Definitive	Autosomal recessive
primary ciliary dyskinesia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
primary ciliary dyskinesia 28	Definitive	AR

Mondo (4): primary ciliary dyskinesia 28 (MONDO:0014216), primary ciliary dyskinesia (MONDO:0016575), primary ciliary dyskinesia 1 (MONDO:0009484), autosomal dominant nocturnal frontal lobe epilepsy 5 (MONDO:0014002)

Orphanet (3): Primary ciliary dyskinesia (Orphanet:244), Sleep-related hypermotor epilepsy (Orphanet:98784), Primary ciliary dyskinesia, Kartagener type (Orphanet:98861)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000119	Abnormality of the genitourinary system
HP:0000238	Hydrocephalus
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000750	Delayed speech and language development
HP:0000924	Abnormality of the skeletal system
HP:0001217	Clubbing
HP:0001627	Abnormal heart morphology
HP:0001669	Transposition of the great arteries
HP:0001696	Situs inversus totalis
HP:0001719	Double outlet right ventricle
HP:0001742	Nasal congestion
HP:0001746	Asplenia
HP:0001748	Polysplenia
HP:0002011	Morphological central nervous system abnormality
HP:0002110	Bronchiectasis
HP:0002119	Ventriculomegaly
HP:0002205	Recurrent respiratory infections
HP:0002257	Chronic rhinitis
HP:0002566	Intestinal malrotation
HP:0002643	Neonatal respiratory distress
HP:0002878	Respiratory failure
HP:0003251	Male infertility
HP:0004469	Chronic bronchitis
HP:0005301	Persistent left superior vena cava
HP:0005425	Recurrent sinopulmonary infections

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002389_182	Lymphocyte percentage of white cells	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
Benzo(a)pyrene	increases expression	4
Aflatoxin B1	affects expression, increases expression, increases methylation	4
Cyclosporine	increases expression, decreases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Palmitic Acid	decreases expression, decreases phosphorylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
arsenite	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	affects cotreatment, increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Amiodarone	increases expression	1
Vehicle Emissions	increases expression, increases abundance	1

Clinical trials (associated diseases)

71 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide
NCT00783887	Not specified	COMPLETED	Diagnosis of Primary Ciliary Dyskinesia
NCT00807482	Not specified	RECRUITING	Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
NCT01070914	Not specified	UNKNOWN	Early Detection and Characterization of Primary Ciliary Dyskinesia
NCT01155115	Not specified	COMPLETED	Inflammatory and Microbiologic Markers in Sputum: Comparing Cystic Fibrosis With Primary Ciliary Dyskinesia
NCT01246258	Not specified	COMPLETED	Otolith Function in Patients With Primary Ciliary Dyskinesia
NCT01929356	Not specified	RECRUITING	Chest Physiotherapy and Lung Function in Primary Ciliary Dyskinesia
NCT02389049	Not specified	COMPLETED	Genetics of Primary Ciliary Dyskinesia
NCT02419365	Not specified	RECRUITING	International Primary Ciliary Dyskinesia (PCD) Registry
NCT02699177	Not specified	UNKNOWN	In Vivo Measurements of Nasal Ciliary Beat Frequency by Using Interferometry
NCT02704455	Not specified	NOT_YET_RECRUITING	Registry Study on Primary Ciliary Dyskinesia in Chinese Children
NCT03271840	Not specified	COMPLETED	Registry for Primary Ciliary Dyskinesia
NCT03279965	Not specified	UNKNOWN	MRI in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03320382	Not specified	UNKNOWN	Multiple Breath Washout, a Clinimetric Dataset
NCT03370029	Not specified	COMPLETED	Respiratory Muscle Strength, Exercise Capacity and Physical Activity Levels in Children Primary Ciliary Dyskinesia
NCT03494894	Not specified	COMPLETED	Bacteriological Link Between Upper and Lower Airways in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03517865	Not specified	ACTIVE_NOT_RECRUITING	International Primary Ciliary Dyskinesia Cohort
NCT03606200	Not specified	RECRUITING	Swiss Primary Ciliary Dyskinesia Registry
NCT03704207	Not specified	RECRUITING	Utility of PCD Diagnostics to Improve Clinical Care
NCT03704896	Not specified	UNKNOWN	PRospective Observational Multicentre Study on VAriability of Lung Function in Stable PCD Patients
NCT03801395	Not specified	COMPLETED	PCD New Gene Discovery
NCT03809091	Not specified	UNKNOWN	WGS of Korean Idiopathic Bronchiectasis
NCT03832491	Not specified	COMPLETED	Effect of Game Based Approach on Oxygenation, Functional Capacity and Quality of Life in Primary Ciliary Dyskinesia
NCT04161313	Not specified	COMPLETED	Respiratory Function, Exercise Capacity and Peripheral Muscle Strength Among Patients With CF, PCD and Healthy Children
NCT04476433	Not specified	COMPLETED	Intervention in Chronic Pediatric Patients and Their Families.
NCT04489472	Not specified	UNKNOWN	The Effect of a Dietary Supplement Rich in Nitric Oxide in Patients Diagnosed With Primary Ciliary Dyskinesia.
NCT04602481	Not specified	RECRUITING	Living With Primary Ciliary Dyskinesia (Living With PCD)