CEP135

Summary

CEP135 (centrosomal protein 135, HGNC:29086) is a protein-coding gene on chromosome 4q12, encoding Centrosomal protein of 135 kDa (Q66GS9). Centrosomal microtubule-binding protein involved in centriole biogenesis. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8.

Source: NCBI Gene 9662 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly 8, primary, autosomal recessive (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 614 total — 35 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 21
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_025009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29086
Approved symbol	CEP135
Name	centrosomal protein 135
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13621
Ensembl gene	ENSG00000174799
Ensembl biotype	protein_coding
OMIM	611423
Entrez	9662

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 5 retained_intron

ENST00000257287, ENST00000422247, ENST00000506202, ENST00000506809, ENST00000515081, ENST00000706800, ENST00000706801, ENST00000916104, ENST00000916105, ENST00000916106, ENST00000916107

RefSeq mRNA: 1 — MANE Select: NM_025009 NM_025009

CCDS: CCDS33986

Canonical transcript exons

ENST00000257287 — 26 exons

Exon	Start	End
ENSE00001187805	55965644	55965859
ENSE00001405966	55953085	55953275
ENSE00001414480	55954216	55954383
ENSE00001436739	55952086	55952243
ENSE00002020575	55948945	55949059
ENSE00002020999	56031360	56033361
ENSE00003470754	56019353	56019555
ENSE00003474210	55991934	55992085
ENSE00003488654	55999302	55999417
ENSE00003490620	56017648	56017857
ENSE00003505361	56020676	56020780
ENSE00003527036	55969063	55969128
ENSE00003527941	56024501	56024614
ENSE00003543427	55974746	55974969
ENSE00003548685	55957223	55957364
ENSE00003558136	56009735	56009903
ENSE00003580499	55985281	55985358
ENSE00003605718	55971270	55971408
ENSE00003618403	55980143	55980295
ENSE00003619678	55999491	55999645
ENSE00003638399	56011800	56011985
ENSE00003642109	56008327	56008382
ENSE00003654636	55964274	55964402
ENSE00003683003	56011412	56011522
ENSE00003685611	55981227	55981379
ENSE00003693030	55959682	55959766

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 89.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.2858 / max 128.3385, expressed in 1660 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47705	3.5171	1426
47707	2.3057	1039
47706	1.3509	791
47708	0.1121	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	89.54	gold quality
buccal mucosa cell	CL:0002336	88.81	gold quality
sperm	CL:0000019	88.77	gold quality
ventricular zone	UBERON:0003053	87.20	gold quality
male germ cell	CL:0000015	86.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.56	gold quality
bone marrow	UBERON:0002371	81.49	gold quality
monocyte	CL:0000576	81.38	gold quality
mononuclear cell	CL:0000842	81.25	gold quality
leukocyte	CL:0000738	80.92	gold quality
calcaneal tendon	UBERON:0003701	80.48	gold quality
secondary oocyte	CL:0000655	79.23	gold quality
lymph node	UBERON:0000029	79.23	gold quality
epithelium of nasopharynx	UBERON:0001951	79.03	gold quality
ganglionic eminence	UBERON:0004023	79.02	gold quality
bone marrow cell	CL:0002092	78.98	gold quality
bronchial epithelial cell	CL:0002328	78.70	gold quality
trabecular bone tissue	UBERON:0002483	78.65	gold quality
vermiform appendix	UBERON:0001154	78.30	gold quality
embryo	UBERON:0000922	78.13	gold quality
body of uterus	UBERON:0009853	78.13	gold quality
endometrium	UBERON:0001295	77.98	gold quality
esophagus squamous epithelium	UBERON:0006920	77.59	silver quality
stromal cell of endometrium	CL:0002255	77.37	gold quality
uterus	UBERON:0000995	76.80	gold quality
blood vessel layer	UBERON:0004797	76.72	gold quality
placenta	UBERON:0001987	76.62	gold quality
superficial temporal artery	UBERON:0001614	76.39	silver quality
myometrium	UBERON:0001296	76.33	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.50
E-MTAB-7381	no	557.27
E-MTAB-8060	no	49.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

152 targeting CEP135, 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-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-433-3P	99.98	69.37	1203
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• CEP135 acts as a platform protein for C-NAP1 at the centriole. (PMID:18851962)
• A truncating mutation of CEP135 caused autosomal-recessive primary microcephaly in a Pakistani family. (PMID:22521416)
• Authors propose that CEP135 directly connects the central hub protein, hSAS-6, to the outer microtubules, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. (PMID:23511974)
• These findings support a model in which PKC-mediated phosphorylation of CEP4 at Ser(18) and Ser(80) causes its dissociation from Cdc42, thereby increasing its affinity for TEM4 and producing Rac activation, filopodium formation, and cell motility (PMID:25086031)
• Authors suggest that the decrease in CEP135(mini) from centrosomes promotes centriole assembly. The repression of centriole duplication by a splice isoform of a protein that normally promotes it serves as a novel mechanism to limit centriole duplication. (PMID:26412126)
• identified the second mutation in CEP135, confirming the role during embryonic brain development and in the pathophysiology of human primary microcephaly (PMID:26657937)
• CEP135 segment 96-108 is a major microtubule-binding site. (PMID:27477386)
• The analysis of the distribution of genotypes in CEP135 rs4865047 and NPY2R rs1902491 detected significant differences only in the single nucleotide polymorphism rs4865047 genotype between the case and control group in comparison to the reference group. The co-dominant model showed that CEP135 rs4865047 was significantly associated with patients with rapidly progressive proliferative diabetic retinopathy (PMID:30531682)
• Dysregulation of CEP135 isoforms promotes centriole overduplication and contributes to chromosome segregation errors in breast cancer cells. (PMID:30811267)
• Mutation in CEP135 causing primary microcephaly and subcortical heterotopia. (PMID:32643282)
• Mitotic Maturation Compensates for Premature Centrosome Splitting and PCM Loss in Human cep135 Knockout Cells. (PMID:35406752)
• Centrosomal Protein CEP135 Regulates the Migration and Angiogenesis of Endothelial Cells in a Microtubule-Dependent Manner. (PMID:38062802)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cep135	ENSMUSG00000036403
rattus_norvegicus	Cep135	ENSRNOG00000002153

Paralogs (4): CROCC (ENSG00000058453), CEP250 (ENSG00000126001), TSGA10 (ENSG00000135951), CROCC2 (ENSG00000226321)

Protein

Protein identifiers

Centrosomal protein of 135 kDa — Q66GS9 (reviewed: Q66GS9)

Alternative names: Centrosomal protein 4

All UniProt accessions (1): Q66GS9

UniProt curated annotations — full annotation on UniProt →

Function. Centrosomal microtubule-binding protein involved in centriole biogenesis. Acts as a scaffolding protein during early centriole biogenesis. Required for the targeting of centriole satellite proteins to centrosomes such as of PCM1, SSX2IP and CEP290 and recruitment of WRAP73 to centrioles. Also required for centriole-centriole cohesion during interphase by acting as a platform protein for CEP250 at the centriole. Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner.

Subunit / interactions. Homodimer. Interacts with DCTN2. Interacts with CEP250.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole.

Disease relevance. Microcephaly 8, primary, autosomal recessive (MCPH8) [MIM:614673] A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals have severe intellectual disability. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Coiled-coil domains are critical for microtubule binding via the formation of a two-stranded coiled-coil structure in homodimers.

Similarity. Belongs to the CEP135/TSGA10 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q66GS9-1	1	yes
Q66GS9-2	2

RefSeq proteins (1): NP_079285* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR051877	Centriole_BasalBody_StrucProt	Family

UniProt features (27 total): modified residue 5, coiled-coil region 5, site 3, mutagenesis site 3, region of interest 2, splice variant 2, sequence conflict 2, chain 1, disulfide bond 1, sequence variant 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5FCN	X-RAY DIFFRACTION	1.8
5NG4	X-RAY DIFFRACTION	2.14

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q66GS9-F1	77.15	0.09

Functional residue map

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

Catalytic / active sites (3): 104 (microtubule binding); 108 (microtubule binding); 101 (microtubule binding)

Post-translational modifications (5): 383, 439, 688, 1121, 1130

Disulfide bonds (1): 110

Mutagenesis-validated functional residues (3):

Position	Phenotype
101	reduced microtubule binding ability but normal coiled-coil homodimerization; when associated with a-104 and a-108.
104	reduced microtubule binding ability but normal coiled-coil homodimerization; when associated with a-101 and a-108.
108	reduced microtubule binding ability but normal coiled-coil homodimerization; when associated with a-101 and a-104.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-380259	Loss of Nlp from mitotic centrosomes
R-HSA-380270	Recruitment of mitotic centrosome proteins and complexes
R-HSA-380284	Loss of proteins required for interphase microtubule organization from the centrosome
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-8854518	AURKA Activation by TPX2

MSigDB gene sets: 279 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, MODULE_45, MORF_ATRX, MORF_ESR1, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_66, MODULE_118, GOBP_CENTRIOLE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MODULE_379, GOBP_CILIUM_ORGANIZATION

GO Biological Process (4): centriole replication (GO:0007099), centriole-centriole cohesion (GO:0010457), positive regulation of non-motile cilium assembly (GO:1902857), positive regulation of establishment of protein localization (GO:1904951)

GO Molecular Function (5): microtubule binding (GO:0008017), tubulin binding (GO:0015631), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (5): centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
G2/M Transition	2
Centrosome maturation	2
Loss of proteins required for interphase microtubule organization from the centrosome	1
Mitotic Prometaphase	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell cycle process	2
microtubule organizing center	2
intracellular membraneless organelle	2
cellular anatomical structure	2
centrosome duplication	1
centriole assembly	1
centrosome cycle	1
positive regulation of cilium assembly	1
regulation of non-motile cilium assembly	1
non-motile cilium assembly	1
establishment of protein localization	1
positive regulation of biological process	1
regulation of establishment of protein localization	1
tubulin binding	1
cytoskeletal protein binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
centriole	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1709 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CEP135	SASS6	Q6UVJ0	999
CEP135	CPAP	Q9HC77	993
CEP135	PLK4	O00444	982
CEP135	CCP110	O43303	954
CEP135	STIL	Q15468	951
CEP135	CEP152	O94986	942
CEP135	CNTLN	Q9NXG0	870
CEP135	TUBG1	P23258	845
CEP135	CEP295	Q9C0D2	845
CEP135	CETN2	P41208	840
CEP135	CEP192	Q8TEP8	827
CEP135	PCNT	O95613	821
CEP135	CNTROB	Q8N137	819
CEP135	CEP63	Q96MT8	794
CEP135	WDR62	O43379	768
CEP135	CDK5RAP2	Q96SN8	768

IntAct

98 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
WRAP73	CEP135	psi-mi:“MI:0914”(association)	0.890
CEP135	CPAP	psi-mi:“MI:0403”(colocalization)	0.700
CPAP	CEP135	psi-mi:“MI:0914”(association)	0.700
CPAP	CEP135	psi-mi:“MI:0915”(physical association)	0.700
CEP135	CPAP	psi-mi:“MI:0915”(physical association)	0.700
CPAP	CEP135	psi-mi:“MI:0407”(direct interaction)	0.700
CEP135	CPAP	psi-mi:“MI:0407”(direct interaction)	0.700
SASS6	CEP135	psi-mi:“MI:0915”(physical association)	0.650
CEP135	SASS6	psi-mi:“MI:0915”(physical association)	0.650
CEP135	SASS6	psi-mi:“MI:0407”(direct interaction)	0.650
SASS6	CEP135	psi-mi:“MI:0914”(association)	0.650
MIS18A	DCTN6	psi-mi:“MI:0914”(association)	0.640
CEP135	PIBF1	psi-mi:“MI:0915”(physical association)	0.560
PIBF1	CEP135	psi-mi:“MI:0915”(physical association)	0.560
CEP162	CEP135	psi-mi:“MI:0915”(physical association)	0.540
CEP135	SPICE1	psi-mi:“MI:0914”(association)	0.540
CEP135	SPICE1	psi-mi:“MI:0915”(physical association)	0.540
CEP135	RC3H1	psi-mi:“MI:0915”(physical association)	0.540
CEP135	RC3H1	psi-mi:“MI:0403”(colocalization)	0.540
BORCS6	HSBP1	psi-mi:“MI:0914”(association)	0.530
TXLNB	LAMC1	psi-mi:“MI:0914”(association)	0.530

BioGRID (419): CEP135 (Affinity Capture-MS), CEP135 (Affinity Capture-MS), CEP135 (Affinity Capture-MS), CEP135 (Proximity Label-MS), CEP135 (Affinity Capture-Western), CEP162 (Affinity Capture-Western), WRAP73 (Affinity Capture-MS), XKR4 (Affinity Capture-MS), AIMP1 (Affinity Capture-MS), MAPRE1 (Affinity Capture-MS), SPATA5 (Affinity Capture-MS), SREK1 (Affinity Capture-MS), SREK1IP1 (Affinity Capture-MS), ZMAT2 (Affinity Capture-MS), CEP135 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QCI3, A0JMK8, A3KGV1, A7YH32, A9X1A5, B0KWC9, B6MFW3, B8JK76, G5E861, G9G127, O35550, O35551, P59242, P85120, Q15276, Q3V6T2, Q502I3, Q5BJF6, Q5RG45, Q5SNZ0, Q5TZ80, Q5ZJ27, Q5ZKK5, Q66GS9, Q66KE8, Q6AYX5, Q6DIX6, Q6NRB0, Q6P402, Q6P5D4, Q6PGZ0, Q6VGS5, Q6ZU80, Q7TMK6, Q80UF4, Q80YF0, Q80YT7, Q86SQ7, Q8BIL5, Q8CJ99

Diamond homologs: A8ID55, Q66GS9, Q4R6W3, Q5RG45, Q6NY15, Q6P5D4, Q9BZW7, Q9Z220

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CEP135	“up-regulates activity”	SASS6	binding
CEP135	“up-regulates activity”	CENPJ	binding
CEP135	“up-regulates activity”	Tubulin	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
Loss of Nlp from mitotic centrosomes	13	35.5×	4e-15
Loss of proteins required for interphase microtubule organization from the centrosome	13	35.5×	4e-15
AURKA Activation by TPX2	13	34.1×	5e-15
Recruitment of mitotic centrosome proteins and complexes	13	30.5×	1e-14
Regulation of PLK1 Activity at G2/M Transition	13	28.4×	3e-14
Anchoring of the basal body to the plasma membrane	14	27.3×	5e-15
Recruitment of NuMA to mitotic centrosomes	13	26.1×	8e-14
Centrosome maturation	5	21.9×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
centriole replication	6	57.8×	2e-07
non-motile cilium assembly	7	26.8×	1e-06
cilium assembly	15	14.5×	5e-11
chromosome segregation	5	11.4×	4e-03
cell division	8	4.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	17
Uncertain significance	250
Likely benign	202
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012268	NM_025009.5(CEP135):c.2863C>T (p.Arg955Ter)	Pathogenic
1012269	NM_025009.5(CEP135):c.1376_1379del (p.Lys459fs)	Pathogenic
1394922	NM_025009.5(CEP135):c.940A>T (p.Lys314Ter)	Pathogenic
1423979	NM_025009.5(CEP135):c.2584del (p.Val862fs)	Pathogenic
1452171	NM_025009.5(CEP135):c.3042del (p.Glu1015fs)	Pathogenic
1455882	NM_025009.5(CEP135):c.2131_2134dup (p.Asn712fs)	Pathogenic
1456336	NM_025009.5(CEP135):c.1132G>T (p.Glu378Ter)	Pathogenic
1526125	NM_025009.5(CEP135):c.3118_3121del (p.Asn1040fs)	Pathogenic
1942878	NM_025009.5(CEP135):c.2071del (p.Arg691fs)	Pathogenic
2036626	NM_025009.5(CEP135):c.1615_1616del (p.Leu539fs)	Pathogenic
2048259	NM_025009.5(CEP135):c.1092_1093del (p.Met365fs)	Pathogenic
2082848	NM_025009.5(CEP135):c.2214del (p.Leu739fs)	Pathogenic
2101168	NM_025009.5(CEP135):c.935dup (p.Asn312fs)	Pathogenic
2105088	NM_025009.5(CEP135):c.2545_2546del (p.Glu849fs)	Pathogenic
2173838	NM_025009.5(CEP135):c.2500_2501dup (p.Asn834fs)	Pathogenic
2185340	NM_025009.5(CEP135):c.1733T>G (p.Leu578Ter)	Pathogenic
2819957	NM_025009.5(CEP135):c.1138del (p.Glu380fs)	Pathogenic
2894595	NM_025009.5(CEP135):c.727C>T (p.Arg243Ter)	Pathogenic
2959347	NM_025009.5(CEP135):c.1360C>T (p.Arg454Ter)	Pathogenic
2983387	NM_025009.5(CEP135):c.1827_1830del (p.Ile610fs)	Pathogenic
31661	NM_025009.5(CEP135):c.970del (p.Gln324fs)	Pathogenic
3389843	NM_025009.5(CEP135):c.2928dup (p.Leu977fs)	Pathogenic
3613095	NM_025009.5(CEP135):c.2764C>T (p.Arg922Ter)	Pathogenic
3722649	NM_025009.5(CEP135):c.1447del (p.Ser483fs)	Pathogenic
417785	NM_025009.5(CEP135):c.1473+1G>A	Pathogenic
4225921	NM_025009.5(CEP135):c.1487C>G (p.Ser496Ter)	Pathogenic
4279703	NM_025009.5(CEP135):c.2501dup (p.Asn834fs)	Pathogenic
433185	NM_025009.5(CEP135):c.2930_2931del (p.Leu977fs)	Pathogenic
4734928	NM_025009.5(CEP135):c.1368T>G (p.Tyr456Ter)	Pathogenic
4752169	NM_025009.5(CEP135):c.1252C>T (p.Arg418Ter)	Pathogenic

SpliceAI

3764 predictions. Top by Δscore:

Variant	Effect	Δscore
4:55949056:GCCG:G	donor_gain	1.0000
4:55949057:CCGGT:C	donor_loss	1.0000
4:55949058:CGG:C	donor_loss	1.0000
4:55949059:GGTG:G	donor_loss	1.0000
4:55949060:G:GA	donor_loss	1.0000
4:55949060:G:GG	donor_gain	1.0000
4:55952080:TCTCA:T	acceptor_loss	1.0000
4:55952081:CTCA:C	acceptor_loss	1.0000
4:55952083:CAGG:C	acceptor_loss	1.0000
4:55953083:A:AG	acceptor_gain	1.0000
4:55953083:AGC:A	acceptor_gain	1.0000
4:55953084:G:GC	acceptor_gain	1.0000
4:55953084:GC:G	acceptor_gain	1.0000
4:55953084:GCG:G	acceptor_gain	1.0000
4:55953084:GCGA:G	acceptor_gain	1.0000
4:55953084:GCGAC:G	acceptor_gain	1.0000
4:55953085:C:CA	acceptor_gain	1.0000
4:55953271:TAAAG:T	donor_gain	1.0000
4:55953272:AAAG:A	donor_gain	1.0000
4:55953272:AAAGG:A	donor_loss	1.0000
4:55953273:AAG:A	donor_gain	1.0000
4:55953274:AG:A	donor_gain	1.0000
4:55953274:AGG:A	donor_loss	1.0000
4:55953275:GG:G	donor_gain	1.0000
4:55953275:GGTA:G	donor_loss	1.0000
4:55953276:G:GG	donor_gain	1.0000
4:55953276:GTAA:G	donor_loss	1.0000
4:55954208:A:AG	acceptor_gain	1.0000
4:55954209:T:G	acceptor_gain	1.0000
4:55954213:A:AG	acceptor_gain	1.0000

AlphaMissense

7519 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:56011915:T:C	L911P	0.997
4:56017796:T:C	L984P	0.996
4:56019438:T:C	L1033P	0.996
4:56020780:G:C	R1107P	0.996
4:55952177:T:C	L16P	0.995
4:55952237:T:C	L36P	0.995
4:55974857:G:C	R454P	0.995
4:56017784:T:C	L980P	0.995
4:55954345:T:C	L145P	0.993
4:55957354:G:C	A202P	0.993
4:55959693:T:C	L209P	0.993
4:56011945:T:C	L921P	0.992
4:56017657:G:C	A938P	0.991
4:55952191:T:G	Y21D	0.990
4:55954261:T:C	L117P	0.990
4:56011872:G:C	A897P	0.990
4:55965654:T:C	L280P	0.989
4:55999581:T:C	L739P	0.989
4:56019522:T:C	L1061P	0.989
4:55953111:T:C	L47P	0.988
4:55954270:T:C	L120P	0.988
4:55965833:G:C	A340P	0.988
4:55965854:G:C	A347P	0.988
4:56011881:G:C	A900P	0.988
4:56019408:T:C	L1023P	0.988
4:55952177:T:A	L16Q	0.987
4:55964302:G:C	R243P	0.987
4:56009878:T:C	L827P	0.986
4:56011909:T:C	L909P	0.986
4:55953114:G:C	R48P	0.985

dbSNP variants (sampled 300 via entrez): RS1000034325 (4:56005672 A>G), RS1000092702 (4:55960787 G>A), RS1000096033 (4:56005125 C>T), RS1000117225 (4:55997053 C>T), RS1000174737 (4:55950877 A>G), RS1000178496 (4:55999382 C>T), RS1000191246 (4:55995302 C>G), RS1000207780 (4:56014999 G>A), RS1000248230 (4:55983929 T>A), RS1000303447 (4:55970295 A>G), RS1000392677 (4:55976612 T>C), RS1000401910 (4:56021282 C>T), RS10004239 (4:55994907 A>G), RS1000434046 (4:55948186 T>C), RS1000467201 (4:55993033 A>G)

Disease associations

OMIM: gene MIM:611423 | disease phenotypes: MIM:614673

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly 8, primary, autosomal recessive	Strong	Autosomal recessive
autosomal recessive primary microcephaly	Supportive	Autosomal recessive

Mondo (2): microcephaly 8, primary, autosomal recessive (MONDO:0013849), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (1): Autosomal recessive primary microcephaly (Orphanet:2512)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000122	Unilateral renal agenesis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000340	Sloping forehead
HP:0000582	Upslanted palpebral fissure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0003103	Abnormal cortical bone morphology
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007333	Hypoplasia of the frontal lobes
HP:0010864	Severe intellectual disability
HP:0011451	Primary microcephaly

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003518_83	Daytime sleep phenotypes	6.000000e-06
GCST005962_39	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST006444_20	Bone mineral density (hip)	8.000000e-06
GCST006445_1	Femoral neck bone mineral density	6.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007702	hip bone mineral density
EFO:0007785	femoral neck bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C579935	Autosomal Recessive Primary Microcephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
tamibarotene	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	decreases expression, affects cotreatment	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Clorgyline	increases expression	1
Copper	increases expression, affects binding	1
Demecolcine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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