TUBGCP4

Summary

TUBGCP4 (tubulin gamma complex component 4, HGNC:16691) is a protein-coding gene on chromosome 15q15.3, encoding Gamma-tubulin complex component 4 (Q9UGJ1). Component of the gamma-tubulin ring complex (gTuRC) which mediates microtubule nucleation. It is a common-essential gene (DepMap: required in 98.6% of cancer cell lines).

This gene encodes a component of the gamma-tubulin ring complex, which is required for microtubule nucleation. In mammalian cells, the protein localizes to centrosomes in association with gamma-tubulin. Crystal structure analysis revealed a structure composed of five helical bundles arranged around conserved hydrophobic cores. An exposed surface area located in the C-terminal domain is essential and sufficient for direct binding to gamma-tubulin. Mutations in this gene that alter microtubule organization are associated with microcephaly and chorioretinopathy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 27229 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly and chorioretinopathy 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 501 total — 29 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_014444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16691
Approved symbol	TUBGCP4
Name	tubulin gamma complex component 4
Location	15q15.3
Locus type	gene with protein product
Status	Approved
Aliases	76P, FLJ14797, GCP4
Ensembl gene	ENSG00000137822
Ensembl biotype	protein_coding
OMIM	609610
Entrez	27229

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000260383, ENST00000561691, ENST00000562053, ENST00000563147, ENST00000563412, ENST00000563517, ENST00000563963, ENST00000564079, ENST00000564511, ENST00000565548, ENST00000566251, ENST00000570081, ENST00000852301, ENST00000852302, ENST00000852303, ENST00000852304, ENST00000938499, ENST00000938500, ENST00000966488, ENST00000966489, ENST00000966490

RefSeq mRNA: 2 — MANE Select: NM_014444 NM_001286414, NM_014444

CCDS: CCDS42030, CCDS66745

Canonical transcript exons

ENST00000564079 — 18 exons

Exon	Start	End
ENSE00000931173	43386206	43386330
ENSE00000931174	43395107	43395157
ENSE00000931175	43395583	43395688
ENSE00000942012	43376503	43376625
ENSE00000942017	43385791	43385956
ENSE00002581581	43405202	43409771
ENSE00003464630	43398041	43398179
ENSE00003480335	43403683	43403799
ENSE00003507951	43400044	43400221
ENSE00003564738	43377014	43377067
ENSE00003578179	43383303	43383504
ENSE00003595328	43397214	43397321
ENSE00003606572	43404413	43404552
ENSE00003615126	43401716	43401850
ENSE00003615378	43376098	43376226
ENSE00003671230	43377847	43377903
ENSE00003680177	43380084	43380163
ENSE00003900917	43371101	43371432

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 91.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1835 / max 105.5654, expressed in 1736 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146299	9.1783	1736
146298	0.0051	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	91.15	gold quality
secondary oocyte	CL:0000655	87.90	gold quality
male germ cell	CL:0000015	87.61	gold quality
buccal mucosa cell	CL:0002336	85.93	gold quality
ganglionic eminence	UBERON:0004023	85.37	gold quality
oocyte	CL:0000023	85.18	gold quality
ventricular zone	UBERON:0003053	85.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.46	gold quality
tibialis anterior	UBERON:0001385	84.21	silver quality
colonic epithelium	UBERON:0000397	83.78	gold quality
cerebellar hemisphere	UBERON:0002245	83.28	gold quality
cerebellar cortex	UBERON:0002129	83.16	gold quality
superficial temporal artery	UBERON:0001614	82.94	silver quality
gastrocnemius	UBERON:0001388	82.82	gold quality
bone marrow cell	CL:0002092	82.66	gold quality
muscle of leg	UBERON:0001383	82.63	gold quality
cortical plate	UBERON:0005343	82.60	gold quality
cerebellum	UBERON:0002037	82.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.44	gold quality
prefrontal cortex	UBERON:0000451	81.97	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.35	gold quality
epithelium of nasopharynx	UBERON:0001951	81.26	silver quality
gingival epithelium	UBERON:0001949	81.10	silver quality
stromal cell of endometrium	CL:0002255	80.96	gold quality
skeletal muscle organ	UBERON:0014892	80.87	gold quality
muscle organ	UBERON:0001630	80.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	80.75	silver quality
islet of Langerhans	UBERON:0000006	80.57	gold quality
body of pancreas	UBERON:0001150	80.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.14
E-MTAB-6386	no	598.17
E-MTAB-7381	no	112.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting TUBGCP4, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-3182	99.40	68.15	2454

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 6)

• Mutations in TUBGCP4 alter microtubule organization via the gamma-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy. (PMID:25817018)
• Gene essentiality of Tubgcp4: dosage effect and autophagy regulation in retinal photoreceptors. (PMID:31345090)
• Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy. (PMID:33137195)
• Clinical Significance of TUBGCP4 Expression in Hepatocellular Carcinoma. (PMID:36530949)
• Exosomal circTUBGCP4 promotes vascular endothelial cell tipping and colorectal cancer metastasis by activating Akt signaling pathway. (PMID:36793126)
• Microcephaly and chorioretinopathy associated with TUBGCP4: a case report and a review of the literature. (PMID:37038737)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tubgcp4	ENSDARG00000005374
mus_musculus	Tubgcp4	ENSMUSG00000027263
rattus_norvegicus	Tubgcp4	ENSRNOG00000012798
drosophila_melanogaster	Grip75	FBGN0026431
drosophila_melanogaster	t-Grip128	FBGN0052232

Paralogs (4): TUBGCP3 (ENSG00000126216), TUBGCP6 (ENSG00000128159), TUBGCP2 (ENSG00000130640), TUBGCP5 (ENSG00000275835)

Protein

Protein identifiers

Gamma-tubulin complex component 4 — Q9UGJ1 (reviewed: Q9UGJ1)

Alternative names: Gamma-ring complex protein 76 kDa

All UniProt accessions (7): Q9UGJ1, H3BN56, H3BNL9, H3BPU4, H3BQ12, H3BQY4, H3BS59

UniProt curated annotations — full annotation on UniProt →

Function. Component of the gamma-tubulin ring complex (gTuRC) which mediates microtubule nucleation. The gTuRC regulates the minus-end nucleation of alpha-beta tubulin heterodimers that grow into microtubule protafilaments, a critical step in centrosome duplication and spindle formation.

Subunit / interactions. Component of the gamma-tubulin ring complex (gTuRC) consisting of TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6 and gamma-tubulin TUBG1 or TUBG2. TUBGCP2, TUBGCP3, TUBGCP4, TUBGCP5 and TUBGCP6 assemble in a 5:5:2:1:1 stoichiometry; each is associated with a gamma-tubulin, thereby arranging 14 gamma-tubulins in a helical manner. Gamma-tubulin at the first position is blocked by TUBGCP3 at the last position, allowing 13 protafilaments to grow into a microtubule. The gTuRC (via TUBGCP3 and TUBGCP6) interacts with ACTB and MZT1; the interactions form a luminal bridge that stabilizes the initial structure during complex assembly. The gTuRC (via TUBGCP2) interacts with MZT2A/MZT2B and CDK5RAP2 (via CM1 motif); the interactions play a role in gTuRC activation. Interacts with NINL. Interacts with ATF5; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome.

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

Tissue specificity. Ubiquitously expressed.

Disease relevance. Microcephaly and chorioretinopathy, autosomal recessive, 3 (MCCRP3) [MIM:616335] A disorder characterized by congenital microcephaly and chorioretinal dysplasia associated with poor vision and nystagmus. Variable ocular anomalies include microphthalmia, retinal folding, retinal detachment, optic nerve hypoplasia, absence of retinal vessels, round areas of chorioretinal atrophy, and attenuated electroretinogram. Most patients have mild developmental delay and mild learning difficulties. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TUBGCP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UGJ1-1	1	yes
Q9UGJ1-2	2

RefSeq proteins (2): NP_001273343, NP_055259* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007259	GCP	Family
IPR040457	GCP_C	Domain
IPR041470	GCP_N	Domain
IPR042241	GCP_C_sf	Homologous_superfamily

Pfam: PF04130, PF17681

UniProt features (36 total): helix 25, strand 6, turn 2, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
3RIP	X-RAY DIFFRACTION	2.3
8RX1	ELECTRON MICROSCOPY	3.57
8Q62	ELECTRON MICROSCOPY	3.72
7AS4	ELECTRON MICROSCOPY	4.13
6V69	ELECTRON MICROSCOPY	4.2
6V6S	ELECTRON MICROSCOPY	4.3
9QVN	ELECTRON MICROSCOPY	4.7
7QJ0	ELECTRON MICROSCOPY	5.32
9QVM	ELECTRON MICROSCOPY	6.8
7QJ1	ELECTRON MICROSCOPY	7
8VRD	ELECTRON MICROSCOPY	7
7QJD	ELECTRON MICROSCOPY	7.1
7QJ3	ELECTRON MICROSCOPY	7.6
8VRJ	ELECTRON MICROSCOPY	7.7
7QJ6	ELECTRON MICROSCOPY	7.8
7QJE	ELECTRON MICROSCOPY	7.8
7QJ9	ELECTRON MICROSCOPY	8.1
8VRK	ELECTRON MICROSCOPY	8.5
7QJ2	ELECTRON MICROSCOPY	8.6
7QJ5	ELECTRON MICROSCOPY	8.7
7QJ7	ELECTRON MICROSCOPY	8.7
7QJ8	ELECTRON MICROSCOPY	8.7
7QJ4	ELECTRON MICROSCOPY	9
7QJA	ELECTRON MICROSCOPY	9.2
7QJB	ELECTRON MICROSCOPY	9.2
7QJC	ELECTRON MICROSCOPY	16.1
9I8G	ELECTRON MICROSCOPY	22.4
9I8H	ELECTRON MICROSCOPY	23.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGJ1-F1	82.49	0.52

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-380270	Recruitment of mitotic centrosome proteins and complexes
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes

MSigDB gene sets: 251 (showing top): MORF_RAGE, CREL_01, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_MICROTUBULE_NUCLEATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_66, CADWELL_ATG16L1_TARGETS_DN, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_CIS, GOCC_CENTROSOME, GOBP_ORGANELLE_ASSEMBLY, GOBP_MITOTIC_CELL_CYCLE

GO Biological Process (7): mitotic cell cycle (GO:0000278), microtubule nucleation (GO:0007020), cytoplasmic microtubule organization (GO:0031122), spindle assembly (GO:0051225), meiotic cell cycle (GO:0051321), protein-containing complex assembly (GO:0065003), microtubule cytoskeleton organization (GO:0000226)

GO Molecular Function (4): structural constituent of cytoskeleton (GO:0005200), gamma-tubulin binding (GO:0043015), protein binding (GO:0005515), microtubule minus-end binding (GO:0051011)

GO Cellular Component (12): spindle pole (GO:0000922), gamma-tubulin complex (GO:0000930), gamma-tubulin ring complex (GO:0000931), centrosome (GO:0005813), cytosol (GO:0005829), microtubule (GO:0005874), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), recycling endosome (GO:0055037), cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Centrosome maturation	1
Mitotic Prometaphase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cell cycle	2
microtubule cytoskeleton organization	2
cytoskeleton organization	2
cytoskeleton	2
microtubule organizing center	2
microtubule cytoskeleton	2
mitotic nuclear division	1
microtubule polymerization	1
supramolecular fiber organization	1
spindle organization	1
chromosome segregation	1
membraneless organelle assembly	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
cellular component assembly	1
protein-containing complex organization	1
microtubule-based process	1
structural molecule activity	1
tubulin binding	1
binding	1
microtubule binding	1
spindle	1
protein-containing complex	1
gamma-tubulin complex	1
gamma-tubulin small complex	1
centriole	1
cytoplasm	1
polymeric cytoskeletal fiber	1
endosome	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUBGCP4	TUBGCP5	Q96RT8	998
TUBGCP4	TUBGCP6	Q96RT7	991
TUBGCP4	TUBGCP3	Q96CW5	978
TUBGCP4	TUBG1	P23258	929
TUBGCP4	TUBGCP2	Q9BSJ2	927
TUBGCP4	NEDD1	Q8NHV4	899
TUBGCP4	MZT1	Q08AG7	865
TUBGCP4	CDK5RAP2	Q96SN8	785
TUBGCP4	B8ZZ87	B8ZZ87	742
TUBGCP4	LCA5	Q86VQ0	707
TUBGCP4	TUBG2	Q9NRH3	692
TUBGCP4	NME7	Q9Y5B8	688
TUBGCP4	MZT2A	Q6P582	639
TUBGCP4	HAUS1	Q96CS2	629
TUBGCP4	NIN	Q8N4C6	616

IntAct

116 interactions, top by confidence:

A	B	Type	Score
TUBGCP5	TUBG1	psi-mi:“MI:0914”(association)	0.840
TUBG1	TUBGCP3	psi-mi:“MI:0914”(association)	0.790
MZT2B	TUBG1	psi-mi:“MI:0914”(association)	0.770
NME7	TUBG1	psi-mi:“MI:0914”(association)	0.730
TUBG2	TUBGCP3	psi-mi:“MI:0914”(association)	0.640
TUBGCP4	LZTR1	psi-mi:“MI:0915”(physical association)	0.620
GLYCTK	TUBGCP4	psi-mi:“MI:0915”(physical association)	0.560
RNF146	TUBGCP4	psi-mi:“MI:0915”(physical association)	0.560
TUBGCP4	GLYCTK	psi-mi:“MI:0915”(physical association)	0.560
TUBGCP4	RNF146	psi-mi:“MI:0915”(physical association)	0.560
Mzt2	TUBG1	psi-mi:“MI:0914”(association)	0.560
TUBGCP4	LGALS3BP	psi-mi:“MI:0915”(physical association)	0.560
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
CD68	TNPO2	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
FBXW11	AHCYL1	psi-mi:“MI:0914”(association)	0.530
MZT1	PCNT	psi-mi:“MI:0914”(association)	0.530
TUBG2	TCP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (232): TUBGCP4 (Affinity Capture-MS), RNF146 (Two-hybrid), GLYCTK (Two-hybrid), TUBGCP4 (Affinity Capture-MS), TUBGCP4 (Affinity Capture-MS), PAK7 (Two-hybrid), TUBGCP4 (Two-hybrid), TUBGCP4 (Two-hybrid), TUBGCP4 (Two-hybrid), TUBGCP4 (Two-hybrid), SDSL (Two-hybrid), OBFC1 (Two-hybrid), TUBGCP4 (Two-hybrid), RPRD1B (Two-hybrid), TUBGCP4 (Two-hybrid)

ESM2 similar proteins: A4FUD6, A4QNE0, A6QQW8, A7YWD2, A9UHW6, B5KFI0, D3Z8D9, O35841, O75031, O94829, P42694, Q0P5I8, Q28H63, Q28H85, Q2KIP7, Q3UBZ5, Q3UFS0, Q3ZC21, Q4KWZ6, Q568H3, Q5EAQ1, Q5R644, Q5R974, Q5RCC1, Q5ZIC8, Q6AXU7, Q6DFV5, Q6NRL4, Q6P2B1, Q7L5D6, Q801N6, Q8BHL5, Q8CIQ7, Q8IZD9, Q8K0C1, Q8QFR4, Q8R5L3, Q8VE62, Q8VIJ8, Q924Z6

Diamond homologs: Q9D4F8, Q9M350, Q9UGJ1, Q9SC88

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TUBGCP4	“form complex”	“g-TuRC complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 125 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
Centrosome maturation	7	21.4×	5e-06
Recruitment of mitotic centrosome proteins and complexes	11	18.0×	9e-09
Recruitment of NuMA to mitotic centrosomes	11	15.4×	2e-08
Regulation of PLK1 Activity at G2/M Transition	7	10.7×	3e-04
Mitotic G2-G2/M phases	7	10.7×	3e-04
G2/M Transition	7	10.7×	3e-04
Loss of Nlp from mitotic centrosomes	5	9.6×	6e-03
Loss of proteins required for interphase microtubule organization from the centrosome	5	9.6×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
microtubule nucleation	6	33.7×	1e-05
phospholipase C-activating G protein-coupled receptor signaling pathway	7	8.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	9
Uncertain significance	152
Likely benign	256
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071077	NM_014444.5(TUBGCP4):c.979C>T (p.Gln327Ter)	Pathogenic
1072929	NM_014444.5(TUBGCP4):c.1609dup (p.Glu537fs)	Pathogenic
1073583	NM_014444.5(TUBGCP4):c.1615C>T (p.Gln539Ter)	Pathogenic
1397786	NM_014444.5(TUBGCP4):c.679_680del (p.Ile227fs)	Pathogenic
1422459	NM_014444.5(TUBGCP4):c.1192C>T (p.Gln398Ter)	Pathogenic
1459414	NM_014444.5(TUBGCP4):c.1636C>T (p.Gln546Ter)	Pathogenic
1692991	NM_014444.5(TUBGCP4):c.1669C>T (p.Arg557Ter)	Pathogenic
190125	NG_042168.2:g.(35752_37583)(39659?)del	Pathogenic
190126	NM_014444.5(TUBGCP4):c.298del (p.Tyr100fs)	Pathogenic
1952110	NM_014444.5(TUBGCP4):c.595C>T (p.Gln199Ter)	Pathogenic
1962033	NM_014444.5(TUBGCP4):c.888del (p.Gly297fs)	Pathogenic
2007726	NM_014444.5(TUBGCP4):c.56G>A (p.Trp19Ter)	Pathogenic
2023217	NM_014444.5(TUBGCP4):c.801C>A (p.Tyr267Ter)	Pathogenic
2033467	NM_014444.5(TUBGCP4):c.1102del (p.Leu368fs)	Pathogenic
2083463	NM_014444.5(TUBGCP4):c.304C>T (p.Gln102Ter)	Pathogenic
2090185	NM_014444.5(TUBGCP4):c.1196C>A (p.Ser399Ter)	Pathogenic
2116154	NM_014444.5(TUBGCP4):c.1434dup (p.Lys479Ter)	Pathogenic
2124309	NM_014444.5(TUBGCP4):c.1911del (p.Asn638fs)	Pathogenic
2413338	NM_014444.5(TUBGCP4):c.1288C>T (p.Gln430Ter)	Pathogenic
265616	NM_014444.5(TUBGCP4):c.726delinsAA (p.Leu243fs)	Pathogenic
2757298	NM_014444.5(TUBGCP4):c.216dup (p.Pro73fs)	Pathogenic
3659374	NM_014444.5(TUBGCP4):c.1080_1081del (p.Phe360fs)	Pathogenic
3675172	NM_014444.5(TUBGCP4):c.61A>T (p.Lys21Ter)	Pathogenic
4715419	NM_014444.5(TUBGCP4):c.181C>T (p.Gln61Ter)	Pathogenic
4773348	NM_014444.5(TUBGCP4):c.242T>G (p.Leu81Ter)	Pathogenic
4773652	NM_014444.5(TUBGCP4):c.537del (p.His180fs)	Pathogenic
803072	NM_014444.5(TUBGCP4):c.1380G>A (p.Trp460Ter)	Pathogenic
933521	NM_014444.5(TUBGCP4):c.1651C>T (p.Arg551Ter)	Pathogenic
961136	NM_014444.5(TUBGCP4):c.556C>T (p.Gln186Ter)	Pathogenic
1066865	NM_014444.5(TUBGCP4):c.384+1G>T	Likely pathogenic

SpliceAI

3465 predictions. Top by Δscore:

Variant	Effect	Δscore
15:43373392:T:TG	donor_gain	1.0000
15:43373393:A:AA	donor_gain	1.0000
15:43376223:GCAG:G	donor_gain	1.0000
15:43376224:CAG:C	donor_loss	1.0000
15:43376225:AGG:A	donor_loss	1.0000
15:43376226:GG:G	donor_loss	1.0000
15:43376227:G:A	donor_loss	1.0000
15:43376228:T:A	donor_loss	1.0000
15:43376622:AGAGG:A	donor_loss	1.0000
15:43376623:GAG:G	donor_gain	1.0000
15:43376623:GAGGT:G	donor_loss	1.0000
15:43376625:GGTAA:G	donor_loss	1.0000
15:43376626:GT:G	donor_loss	1.0000
15:43376627:T:A	donor_loss	1.0000
15:43377845:A:AG	acceptor_gain	1.0000
15:43377846:G:GG	acceptor_gain	1.0000
15:43380082:A:AG	acceptor_gain	1.0000
15:43380083:G:GG	acceptor_gain	1.0000
15:43380159:GAAAA:G	donor_gain	1.0000
15:43380162:AAG:A	donor_loss	1.0000
15:43380163:AGTA:A	donor_loss	1.0000
15:43380164:G:GG	donor_gain	1.0000
15:43386201:TGCA:T	acceptor_loss	1.0000
15:43386202:GCA:G	acceptor_loss	1.0000
15:43386203:CA:C	acceptor_loss	1.0000
15:43386204:A:AG	acceptor_gain	1.0000
15:43386204:AG:A	acceptor_gain	1.0000
15:43386205:G:GA	acceptor_gain	1.0000
15:43386205:GG:G	acceptor_gain	1.0000
15:43386327:TGAG:T	donor_loss	1.0000

AlphaMissense

4370 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:43383349:T:A	W190R	1.000
15:43383349:T:C	W190R	1.000
15:43383362:G:A	G194E	1.000
15:43385885:C:A	A273D	1.000
15:43385905:G:A	G280R	1.000
15:43385905:G:C	G280R	1.000
15:43385906:G:A	G280E	1.000
15:43385915:T:A	V283D	1.000
15:43395111:T:C	L340P	1.000
15:43398106:T:A	W450R	1.000
15:43398106:T:C	W450R	1.000
15:43398139:T:A	W461R	1.000
15:43398139:T:C	W461R	1.000
15:43398143:C:A	P462Q	1.000
15:43400205:T:C	L528P	1.000
15:43401747:T:C	L544P	1.000
15:43401810:T:C	L565P	1.000
15:43404495:T:C	L645P	1.000
15:43376548:T:G	Y85D	0.999
15:43376593:T:G	Y100D	0.999
15:43380091:G:A	G150D	0.999
15:43380091:G:T	G150V	0.999
15:43383341:T:C	L187P	0.999
15:43383350:G:C	W190S	0.999
15:43383351:G:C	W190C	0.999
15:43383351:G:T	W190C	0.999
15:43383356:T:C	L192P	0.999
15:43383361:G:A	G194R	0.999
15:43383361:G:C	G194R	0.999
15:43383362:G:T	G194V	0.999

dbSNP variants (sampled 300 via entrez): RS1000055246 (15:43391716 C>T), RS1000058470 (15:43401414 T>TGC), RS1000147731 (15:43404608 T>C,G), RS1000317254 (15:43380495 G>A), RS1000381121 (15:43393232 A>G), RS1000440048 (15:43400739 A>G), RS1000654137 (15:43386112 A>C,G), RS1000666830 (15:43393789 T>C), RS1000717144 (15:43393925 T>G), RS1000721994 (15:43399551 G>A,T), RS1000774846 (15:43399141 T>C), RS1000933691 (15:43406027 C>T), RS1001079636 (15:43380722 C>A,G,T), RS1001080196 (15:43374777 C>G,T), RS1001114097 (15:43406420 G>A)

Disease associations

OMIM: gene MIM:609610 | disease phenotypes: MIM:616335

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly and chorioretinopathy 3	Strong	Autosomal recessive
microcephaly and chorioretinopathy 1	Supportive	Autosomal recessive

Mondo (4): microcephaly and chorioretinopathy 3 (MONDO:0014592), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), microcephaly and chorioretinopathy 1 (MONDO:0009624)

Orphanet (1): OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

29 total (30 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000307	Pointed chin
HP:0000340	Sloping forehead
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000499	Abnormal eyelash morphology
HP:0000505	Visual impairment
HP:0000568	Microphthalmia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001511	Intrauterine growth retardation
HP:0001999	Abnormal facial shape
HP:0002120	Cerebral cortical atrophy
HP:0002269	Abnormality of neuronal migration
HP:0002650	Scoliosis
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0004422	Biparietal narrowing
HP:0007360	Aplasia/Hypoplasia of the cerebellum
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007731	Chorioretinal dysplasia
HP:0000556	Retinal dystrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006611_14	HDL cholesterol	6.000000e-26
GCST006613_20	Triglycerides	1.000000e-25
GCST007638_46	Glycine levels	3.000000e-08
GCST90013406_111	Liver enzyme levels (alkaline phosphatase)	3.000000e-33

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0009767	glycine measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067132 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.13	Kd	735.6	nM	CHEMBL5653589
6.05	ED50	895.1	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2149687: Binding affinity to human TUBGCP4 incubated for 45 mins by Kinobead based pull down assay	kd	0.7356	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
Resveratrol	affects cotreatment, increases expression	2
triphenyl phosphate	affects expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	decreases expression, increases abundance	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	increases expression	1
Manganese	decreases expression, increases abundance	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	decreases expression	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
CHEMBL5652729	Binding	Binding affinity to human TUBGCP4 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)

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

Trial	Phase	Status	Title
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01834079	PHASE1/PHASE2	UNKNOWN	Study the Safety and Efficacy of Bone Marrow Derived Autologous Cells for the Treatment of Optic Nerve Disease
NCT04680143	PHASE1/PHASE2	COMPLETED	Systemic Erythropoietin Injection in Patients Having Optic Atrophy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT04580979	Not specified	COMPLETED	Natural History Study of FDXR Mutation-related Mitochondriopathy
NCT04594590	Not specified	COMPLETED	Natural History Study of SLC25A46 Mutation-related Mitochondriopathy
NCT04723160	Not specified	COMPLETED	Computer Aided Diagnosis of Multiple Eye Fundus Diseases From Color Fundus Photograph
NCT06390579	Not specified	COMPLETED	Building Research With Artificial Intelligence in Neuro-Ophthalmology
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models