CFAP410

Summary

CFAP410 (cilia and flagella associated protein 410, HGNC:1260) is a protein-coding gene on chromosome 21q22.3, encoding Cilia- and flagella-associated protein 410 (O43822). Plays a role in cilia formation and/or maintenance.

Four alternatively spliced transcript variants encoding four different isoforms have been found for this nuclear gene. All isoforms contain leucine-rich repeats. Three of these isoforms are mitochondrial proteins and one of them lacks the target peptide, so is not located in mitochondrion. This gene is down-regulated in Down syndrome (DS) brain, which may represent mitochondrial dysfunction in DS patients.

Source: NCBI Gene 755 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 449 total — 34 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 96
• Druggable target: yes
• MANE Select transcript: NM_004928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1260
Approved symbol	CFAP410
Name	cilia and flagella associated protein 410
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	YF5, A2, LRRC76
Ensembl gene	ENSG00000160226
Ensembl biotype	protein_coding
OMIM	603191
Entrez	755

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000325223, ENST00000339818, ENST00000397956, ENST00000462742, ENST00000470196, ENST00000478674, ENST00000496321

RefSeq mRNA: 4 — MANE Select: NM_004928 NM_001271440, NM_001271441, NM_001271442, NM_004928

CCDS: CCDS13709, CCDS59444, CCDS59445

Canonical transcript exons

ENST00000339818 — 7 exons

Exon	Start	End
ENSE00001136472	44328944	44330326
ENSE00003465964	44333033	44333262
ENSE00003567529	44335758	44335804
ENSE00003613299	44337649	44337667
ENSE00003623799	44331843	44332014
ENSE00003670111	44330823	44330919
ENSE00003844272	44339118	44339390

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 96.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5501 / max 80.5955, expressed in 1799 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190745	10.1181	1781
190744	3.4320	1601

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.41	gold quality
adenohypophysis	UBERON:0002196	94.32	gold quality
right frontal lobe	UBERON:0002810	93.18	gold quality
metanephros cortex	UBERON:0010533	93.08	gold quality
right lobe of thyroid gland	UBERON:0001119	92.93	gold quality
left lobe of thyroid gland	UBERON:0001120	92.75	gold quality
nucleus accumbens	UBERON:0001882	92.71	gold quality
pituitary gland	UBERON:0000007	92.68	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.15	gold quality
amygdala	UBERON:0001876	91.85	gold quality
putamen	UBERON:0001874	91.58	gold quality
apex of heart	UBERON:0002098	91.45	gold quality
caudate nucleus	UBERON:0001873	91.32	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.29	gold quality
granulocyte	CL:0000094	91.28	gold quality
cingulate cortex	UBERON:0003027	91.23	gold quality
thyroid gland	UBERON:0002046	91.04	gold quality
left ovary	UBERON:0002119	90.95	gold quality
anterior cingulate cortex	UBERON:0009835	90.95	gold quality
tibial nerve	UBERON:0001323	90.84	gold quality
left uterine tube	UBERON:0001303	90.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.45	gold quality
body of uterus	UBERON:0009853	90.40	gold quality
left testis	UBERON:0004533	90.35	gold quality
right testis	UBERON:0004534	90.28	gold quality
endocervix	UBERON:0000458	90.23	gold quality
spinal cord	UBERON:0002240	90.23	gold quality
prefrontal cortex	UBERON:0000451	90.14	gold quality
body of stomach	UBERON:0001161	90.10	gold quality
right ovary	UBERON:0002118	90.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYOD1

miRNA regulators (miRDB)

27 targeting CFAP410, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-6865-3P	97.54	64.67	684
HSA-MIR-3972	97.19	66.46	808
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3189-3P	96.80	66.34	896

Literature-anchored findings (GeneRIF, showing 10)

• Downregulated protein level of C21orf2 in adult brain of patients with Down syndrome (DS) in contrast to Alzheimer’s disease indicates that it can be considered specific for changes in DS. (PMID:15068244)
• C21ORF2 functions in the same pathway as NEK1 in DNA damage repair. (PMID:26290490)
• This retinal dystrophy phenotype is caused by recessive mutations in C21orf2 and can be considered a retinal ciliopathy as C21orf2 encodes a protein that localises to photoreceptor ciliary structures. (PMID:26294103)
• Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation (PMID:26974433)
• Mutation in C21ORF2 gene is associated with amyotrophic lateral sclerosis. (PMID:27455348)
• reduced levels of functional C21orf2 induced photoreceptor degradation through abnormal cilia formation, leading to arRP or arCRD in the retina. (PMID:27548899)
• Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes.the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations. (PMID:28422394)
• Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases. (PMID:37188479)
• ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons. (PMID:39227882)
• The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body. (PMID:39255848)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cfap410	ENSDARG00000099397
mus_musculus	Cfap410	ENSMUSG00000020284
rattus_norvegicus	Cfap410	ENSRNOG00000001215
drosophila_melanogaster	CG15208	FBGN0030247
drosophila_melanogaster	CG14995	FBGN0035497
caenorhabditis_elegans		WBGENE00017320

Protein

Protein identifiers

Cilia- and flagella-associated protein 410 — O43822 (reviewed: O43822)

Alternative names: C21orf-HUMF09G8.5, Leucine-rich repeat-containing protein 76, YF5/A2

All UniProt accessions (1): O43822

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in cilia formation and/or maintenance. Plays a role in the regulation of cell morphology and cytoskeletal organization. Involved in DNA damage repair.

Subunit / interactions. Found in a complex with CFAP410, NEK1 and SPATA7. Interacts with NEK1.

Subcellular location. Mitochondrion. Cytoplasm. Cytoskeleton. Cilium basal body. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Widely expressed. Expressed in the retina.

Disease relevance. Retinal dystrophy with or without macular staphyloma (RDMS) [MIM:617547] An ocular disorder characterized by decreased vision which worsen over time, and dystrophic changes in the retina, such as retinal pigment epithelium mottling and vessel narrowing. Macular staphyloma, without high myopia, is present in some patients. The disease is caused by variants affecting the gene represented in this entry. Spondylometaphyseal dysplasia, axial (SMDAX) [MIM:602271] A form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDAX is characterized by metaphyseal changes of truncal-juxtatruncal bones, including the proximal femora. Main clinical features are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram. The radiological hallmarks include short ribs with flared, cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
O43822-1	Long	yes
O43822-2	Short
O43822-3	3
O43822-4	4

RefSeq proteins (4): NP_001258369, NP_001258370, NP_001258371, NP_004919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003603	U2A’_phosphoprotein32A_C	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily

UniProt features (27 total): sequence variant 9, splice variant 4, modified residue 4, repeat 3, helix 2, region of interest 2, chain 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8AXR	X-RAY DIFFRACTION	1.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43822-F1	78.77	0.57

Functional residue map

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

Post-translational modifications (4): 177, 177, 136, 177

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 342 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_66, WEI_MYCN_TARGETS_WITH_E_BOX, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_CILIUM_ORGANIZATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_ORGANELLE_ASSEMBLY, MODULE_88, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, GOBP_SMOOTHENED_SIGNALING_PATHWAY, GOCC_NEURON_PROJECTION, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (6): DNA damage response (GO:0006974), cytoskeleton organization (GO:0007010), smoothened signaling pathway (GO:0007224), regulation of cell shape (GO:0008360), cilium assembly (GO:0060271), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): photoreceptor outer segment (GO:0001750), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), photoreceptor connecting cilium (GO:0032391), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), cytoskeleton (GO:0005856), cell projection (GO:0042995), photoreceptor cell cilium (GO:0097733)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
photoreceptor cell cilium	2
intracellular membrane-bounded organelle	2
cilium	2
cellular response to stress	1
organelle organization	1
cell surface receptor signaling pathway	1
regulation of cell morphogenesis	1
regulation of biological quality	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
cellular component organization	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
endomembrane system	1
membrane	1
cell periphery	1
ciliary transition zone	1
microtubule organizing center	1
intracellular membraneless organelle	1
neuron projection	1
9+0 non-motile cilium	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

67 interactions, top by confidence:

A	B	Type	Score
CEP290	CCP110	psi-mi:“MI:2364”(proximity)	0.890
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
CFAP410	ATOX1	psi-mi:“MI:0915”(physical association)	0.560
FLJ13057	CFAP410	psi-mi:“MI:0915”(physical association)	0.560
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
KIF2B	BACH1	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
ODAD4	GNPAT	psi-mi:“MI:0914”(association)	0.530
TEKT4	CLOCK	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
WDR83	SH2B2	psi-mi:“MI:0914”(association)	0.530
CBY1	CFAP410	psi-mi:“MI:0914”(association)	0.510
NEK1	CFAP410	psi-mi:“MI:0914”(association)	0.510
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
Nek1	CFAP410	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
SPATA7	CFAP410	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): C21orf2 (Two-hybrid), GMCL1 (Two-hybrid), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Proximity Label-MS), C21orf2 (Proximity Label-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS), C21orf2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8P0N4K0, A5YM72, A6NIK2, A6NIX2, D3KCC4, D3Z7H8, D3ZU57, O08742, O43822, O75427, O95382, P40197, Q02779, Q13470, Q14160, Q149C3, Q15653, Q16584, Q24K06, Q32P44, Q3UGP9, Q505F5, Q5BKY1, Q5I2M8, Q5RKR3, Q5U651, Q66HA1, Q6EMK4, Q6NSJ5, Q6UXK2, Q6UY18, Q76KP1, Q80U72, Q80XI6, Q80ZD5, Q86WK7, Q8C013, Q8K3W2, Q8N1G4, Q8WUA8

Diamond homologs: B6CZ40, B6CZ45, B6CZ54, B6CZ61, O35125, O43822, P09661, P34390, P57784, Q16RY9, Q28CU0, Q32KP2, Q4R8Y8, Q4V8C9, Q53EV4, Q5EAD8, Q7PK92, Q8IYG6, Q8K375, Q96E66, Q9DAK8, A0A1L8G016, B3DH20, Q09JZ4, Q28FY0, Q6AYH9, Q8CDN9, P43333, Q6NRC9, Q6ZRR7, Q9BLB6, A2ARI4, A6NJW4, A8WHP9, B0BLW3, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	103.8×	2e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	91.6×	3e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	91.6×	3e-09
Activation of BH3-only proteins	6	67.7×	1e-08
RHO GTPases activate PKNs	6	43.3×	1e-07
Intrinsic Pathway for Apoptosis	6	39.9×	2e-07
SARS-CoV-1-host interactions	6	24.0×	4e-06
Apoptosis	6	22.9×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	31.6×	1e-04
intracellular protein localization	9	16.2×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	9
Uncertain significance	181
Likely benign	166
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068944	NM_004928.3(CFAP410):c.528_529insG (p.Ser177fs)	Pathogenic
1360417	NM_004928.3(CFAP410):c.195_196del (p.Ser65fs)	Pathogenic
1388700	NM_004928.3(CFAP410):c.381_396del (p.Glu128fs)	Pathogenic
1413087	NM_004928.3(CFAP410):c.46G>T (p.Glu16Ter)	Pathogenic
1456033	NC_000021.8:g.(?45752896)(45753165_?)del	Pathogenic
1457702	NC_000021.8:g.(?45757512)(45757570_?)del	Pathogenic
1457710	NM_004928.3(CFAP410):c.96+1G>A	Pathogenic
1512365	NM_004928.3(CFAP410):c.545+1G>C	Pathogenic
1683424	NM_004928.3(CFAP410):c.642+2T>C	Pathogenic
1970853	NM_004928.3(CFAP410):c.482dup (p.Ser162fs)	Pathogenic
2024776	NM_004928.3(CFAP410):c.164_168dup (p.Pro57fs)	Pathogenic
2042242	NM_004928.3(CFAP410):c.285_301delinsACCCGTGCACGAACCCGT (p.Glu96fs)	Pathogenic
2627897	NM_004928.3(CFAP410):c.144-6_159del	Pathogenic
2820374	NM_004928.3(CFAP410):c.403_404del (p.Leu135fs)	Pathogenic
2823020	NM_004928.3(CFAP410):c.526del (p.Asp176fs)	Pathogenic
3248185	NC_000021.8:g.(?45743649)(45843615_?)del	Pathogenic
3248186	NC_000021.8:g.(?45750081)(45757570_?)del	Pathogenic
3249463	NM_004928.3(CFAP410):c.285_289del (p.Glu96fs)	Pathogenic
3250351	NC_000021.9:g.(?44330197)(44330920_44331842)del	Pathogenic
428574	NM_004928.3(CFAP410):c.671T>C (p.Leu224Pro)	Pathogenic
428575	NM_004928.3(CFAP410):c.103del (p.Ile35fs)	Pathogenic
428576	NM_004928.3(CFAP410):c.436_466del (p.Glu146fs)	Pathogenic
428578	NM_004928.3(CFAP410):c.545+1G>A	Pathogenic
428580	NM_004928.3(CFAP410):c.319T>C (p.Tyr107His)	Pathogenic
428582	NM_004928.3(CFAP410):c.331G>A (p.Val111Met)	Pathogenic
428583	NM_004928.3(CFAP410):c.320A>G (p.Tyr107Cys)	Pathogenic
438159	NM_004928.3(CFAP410):c.33_34insAGCTGCACAGCGTGCA (p.Ala12fs)	Pathogenic
4692337	NM_004928.3(CFAP410):c.278G>A (p.Trp93Ter)	Pathogenic
4710232	NM_004928.3(CFAP410):c.171_178del (p.Ser59fs)	Pathogenic
489375	NM_004928.3(CFAP410):c.355C>T (p.Gln119Ter)	Pathogenic

SpliceAI

1395 predictions. Top by Δscore:

Variant	Effect	Δscore
21:44330821:AC:A	donor_gain	1.0000
21:44330822:CC:C	donor_gain	1.0000
21:44331780:C:A	donor_gain	1.0000
21:44331842:CGTTG:C	donor_gain	1.0000
21:44331849:T:TA	donor_gain	1.0000
21:44331852:T:TA	donor_gain	1.0000
21:44333028:CCTA:C	donor_loss	1.0000
21:44333029:CTA:C	donor_loss	1.0000
21:44333030:TA:T	donor_loss	1.0000
21:44333031:A:AC	donor_gain	1.0000
21:44333031:A:AT	donor_loss	1.0000
21:44333031:AC:A	donor_gain	1.0000
21:44333032:C:CC	donor_gain	1.0000
21:44333032:CC:C	donor_gain	1.0000
21:44333258:TGACA:T	acceptor_gain	1.0000
21:44333260:ACA:A	acceptor_gain	1.0000
21:44333261:CA:C	acceptor_gain	1.0000
21:44333261:CAC:C	acceptor_gain	1.0000
21:44333263:C:CC	acceptor_gain	1.0000
21:44339117:CCAG:C	donor_gain	1.0000
21:44330323:CGTT:C	acceptor_gain	0.9900
21:44330327:C:CC	acceptor_gain	0.9900
21:44330822:CCCTG:C	donor_gain	0.9900
21:44331743:T:TA	donor_gain	0.9900
21:44331744:C:A	donor_gain	0.9900
21:44331779:C:CA	donor_gain	0.9900
21:44331829:C:A	donor_gain	0.9900
21:44331841:A:AC	donor_gain	0.9900
21:44331842:C:CC	donor_gain	0.9900
21:44331919:G:C	donor_gain	0.9900

AlphaMissense

1631 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:44333256:G:C	N50K	0.999
21:44333256:G:T	N50K	0.999
21:44333257:T:A	N50I	0.999
21:44333041:T:A	D122V	0.998
21:44333115:G:C	N97K	0.998
21:44333115:G:T	N97K	0.998
21:44333117:T:A	N97Y	0.998
21:44333191:T:A	N72I	0.998
21:44339172:A:T	V8D	0.998
21:44333117:T:C	N97D	0.997
21:44333117:T:G	N97H	0.997
21:44333131:A:G	L92P	0.997
21:44333190:G:C	N72K	0.997
21:44333190:G:T	N72K	0.997
21:44333192:T:C	N72D	0.997
21:44333262:A:C	S48R	0.997
21:44333262:A:T	S48R	0.997
21:44335759:T:G	S48R	0.997
21:44339127:A:G	L23P	0.997
21:44333042:C:G	D122H	0.996
21:44333044:A:G	L121P	0.996
21:44333074:A:T	V111E	0.996
21:44333084:G:T	R108S	0.996
21:44333116:T:G	N97T	0.996
21:44333185:A:G	I74T	0.996
21:44333206:A:G	L67P	0.996
21:44337666:C:G	G27R	0.996
21:44339127:A:T	L23H	0.996
21:44333044:A:T	L121Q	0.995
21:44333116:T:A	N97I	0.995

dbSNP variants (sampled 300 via entrez): RS1000080593 (21:44334011 G>C), RS1000676171 (21:44334926 C>T), RS1000695004 (21:44339221 G>A,C), RS1000820324 (21:44334730 T>C), RS1000904720 (21:44330690 C>A), RS1000979799 (21:44339817 T>G), RS1001076083 (21:44335322 T>C), RS1001316315 (21:44338704 T>A,C), RS1001328477 (21:44339631 C>T), RS1001415816 (21:44332602 G>A,C), RS1001521151 (21:44335199 A>G), RS1001565777 (21:44339829 C>G), RS1001681942 (21:44339700 C>A,T), RS1001751336 (21:44333093 G>C,T), RS1002651721 (21:44329036 G>A)

Disease associations

OMIM: gene MIM:603191 | disease phenotypes: MIM:617547, MIM:602271, MIM:240300, MIM:120970, MIM:268000, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
axial spondylometaphyseal dysplasia	Definitive	Autosomal recessive
amyotrophic lateral sclerosis	Supportive	Autosomal dominant
cone-rod dystrophy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
ciliopathy	Definitive	AR
amyotrophic lateral sclerosis	Limited	SD

Mondo (10): inherited retinal dystrophy (MONDO:0019118), retinal dystrophy with or without macular staphyloma (MONDO:0060507), axial spondylometaphyseal dysplasia (MONDO:0011211), autoimmune polyendocrine syndrome type 1 (MONDO:0009411), cone-rod dystrophy (MONDO:0015993), retinitis pigmentosa (MONDO:0019200), cone dystrophy (MONDO:0000455), retinal disorder (MONDO:0005283), Leber congenital amaurosis (MONDO:0018998), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (9): Cone rod dystrophy-short stature syndrome (Orphanet:653709), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Axial spondylometaphyseal dysplasia (Orphanet:168549), Autoimmune polyendocrinopathy type 1 (Orphanet:3453), Cone rod dystrophy (Orphanet:1872), Retinitis pigmentosa (Orphanet:791), Progressive cone dystrophy (Orphanet:1871), Leber congenital amaurosis (Orphanet:65), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

96 total (30 of 96 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000217	Xerostomia
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000556	Retinal dystrophy
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000774	Narrow chest
HP:0000907	Anterior rib cupping
HP:0000926	Platyspondyly
HP:0001105	Retinal atrophy
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001744	Splenomegaly
HP:0001824	Weight loss

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004692_1	Amyotrophic lateral sclerosis	3.000000e-10
GCST005647_5	Amyotrophic lateral sclerosis	2.000000e-14

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C535795	Spondylometaphyseal dysplasia, axial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067028 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	Kd	504.2	nM	CHEMBL5653589
6.24	ED50	574	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147971: Binding affinity to human C21orf2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5042	uM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	affects cotreatment, increases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Zinc	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651013	Binding	Binding affinity to human C21orf2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS