TUBA8

Summary

TUBA8 (tubulin alpha 8, HGNC:12410) is a protein-coding gene on chromosome 22q11.21, encoding Tubulin alpha-8 chain (Q9NY65). Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.

This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 51807 — RefSeq curated summary.

At a glance

• Gene–disease (curated): macrothrombocytopenia, isolated, 2, autosomal dominant (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 376 total — 1 pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• MANE Select transcript: NM_018943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12410
Approved symbol	TUBA8
Name	tubulin alpha 8
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183785
Ensembl biotype	protein_coding
OMIM	605742
Entrez	51807

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000316027, ENST00000330423, ENST00000416740, ENST00000426208, ENST00000608634, ENST00000679481, ENST00000679963, ENST00000680175, ENST00000901605, ENST00000901606, ENST00000901607, ENST00000901608, ENST00000954261

RefSeq mRNA: 2 — MANE Select: NM_018943 NM_001193414, NM_018943

CCDS: CCDS13751, CCDS54495

Canonical transcript exons

ENST00000330423 — 5 exons

Exon	Start	End
ENSE00001539883	18130843	18131732
ENSE00001539912	18110809	18110868
ENSE00003566581	18121479	18121701
ENSE00003570829	18126354	18127034
ENSE00003585148	18124156	18124304

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 98.34.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2316 / max 155.4387, expressed in 403 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191014	0.9220	190
191013	0.7318	197
191011	0.5811	226
191015	0.4382	126
191009	0.2269	111
191012	0.1085	65
191008	0.0880	50
191007	0.0618	33
191016	0.0380	18
191010	0.0354	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.34	gold quality
gastrocnemius	UBERON:0001388	97.46	gold quality
apex of heart	UBERON:0002098	97.33	gold quality
muscle of leg	UBERON:0001383	96.81	gold quality
skeletal muscle organ	UBERON:0014892	96.76	gold quality
right atrium auricular region	UBERON:0006631	96.43	gold quality
heart left ventricle	UBERON:0002084	96.15	gold quality
skeletal muscle tissue	UBERON:0001134	95.60	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.05	gold quality
cerebellum	UBERON:0002037	94.99	gold quality
cerebellar cortex	UBERON:0002129	94.95	gold quality
cerebellar hemisphere	UBERON:0002245	94.94	gold quality
heart	UBERON:0000948	93.34	gold quality
left testis	UBERON:0004533	92.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.27	gold quality
right frontal lobe	UBERON:0002810	92.24	gold quality
superior frontal gyrus	UBERON:0002661	92.11	gold quality
right testis	UBERON:0004534	92.03	gold quality
frontal cortex	UBERON:0001870	91.93	gold quality
prefrontal cortex	UBERON:0000451	91.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.65	gold quality
testis	UBERON:0000473	91.64	gold quality
primary visual cortex	UBERON:0002436	91.14	gold quality
monocyte	CL:0000576	91.02	gold quality
leukocyte	CL:0000738	90.18	gold quality
cerebral cortex	UBERON:0000956	90.16	gold quality
anterior cingulate cortex	UBERON:0009835	89.64	gold quality
telencephalon	UBERON:0001893	88.34	gold quality
brain	UBERON:0000955	88.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	22.40
E-GEOD-111727	no	413.84
E-ANND-3	no	1.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I3

miRNA regulators (miRDB)

22 targeting TUBA8, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-4695-3P	96.71	67.21	836
HSA-MIR-3135A	96.41	65.30	494

Literature-anchored findings (GeneRIF, showing 6)

• Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. (PMID:19896110)
• TUBA8 is expressed at low levels in the developing human brain. (PMID:20466094)
• TUBA8 can play a role in the regulation of cell growth, proliferation, and cell migration in a cell-specific manner in vitro. (PMID:21872825)
• Data provide evidence for a role of TUBA8 in hepatic fibrogenesis and malignancies making it a novel player in non-alcoholic steatohepatitis and hepatocellular carcinoma pathology. (PMID:28063004)
• Low TUBA8 expression is associated with 22q11.2 deletion syndrome. (PMID:30627818)
• Dysregulation of SAA1, TUBA8 and Monocytes Are Key Factors in Ankylosing Spondylitis With Femoral Head Necrosis. (PMID:35126370)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tuba8	ENSMUSG00000030137
rattus_norvegicus	Tuba8	ENSRNOG00000048169

Paralogs (23): TUBG2 (ENSG00000037042), TUBE1 (ENSG00000074935), TUBA3D (ENSG00000075886), TUBB1 (ENSG00000101162), TUBB4A (ENSG00000104833), TUBD1 (ENSG00000108423), TUBA1B (ENSG00000123416), TUBA4A (ENSG00000127824), TUBG1 (ENSG00000131462), TUBB2A (ENSG00000137267), TUBB2B (ENSG00000137285), TUBA3E (ENSG00000152086), TUBA1A (ENSG00000167552), TUBA1C (ENSG00000167553), TUBB8B (ENSG00000173213), TUBB6 (ENSG00000176014), TUBAL3 (ENSG00000178462), TUBB4B (ENSG00000188229), TUBB (ENSG00000196230), TUBA3C (ENSG00000198033), TUBA4B (ENSG00000243910), TUBB3 (ENSG00000258947), TUBB8 (ENSG00000261456)

Protein

Protein identifiers

Tubulin alpha-8 chain — Q9NY65 (reviewed: Q9NY65)

Alternative names: Alpha-tubulin 8, Tubulin alpha chain-like 2

All UniProt accessions (6): A0A7P0T945, A0A7P0TA31, C9J2C0, C9K0S6, Q9NY65, V9GZ17

UniProt curated annotations — full annotation on UniProt →

Function. Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers. Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms. Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin.

Subunit / interactions. Dimer of alpha and beta chains. A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Preferentially expressed in heart, skeletal muscle and testis. Expressed at low levels in the developing brain. Expressed in megakaryocytes and platelets.

Post-translational modifications. Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group. Polyglutamylation plays a key role in microtubule severing by spastin (SPAST). SPAST preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity by SPAST increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Glutamylation is also involved in cilia motility. Some glutamate residues at the C-terminus are monoglycylated but not polyglycylated due to the absence of functional TTLL10 in human. Monoglycylation is mainly limited to tubulin incorporated into cilia and flagella axonemes, which is required for their stability and maintenance. Flagella glycylation controls sperm motility. Both polyglutamylation and monoglycylation can coexist on the same protein on adjacent residues, and lowering glycylation levels increases polyglutamylation, and reciprocally. The C-terminal phenylalanine residue is cleaved by MATCAP1/KIAA0895L.

Disease relevance. Macrothrombocytopenia, isolated, 2, autosomal dominant (MACTHC2) [MIM:619840] A congenital blood disorder characterized by increased platelet size and decreased number of circulating platelets. Affected individuals usually are asymptomatic and do not have increased bleeding episodes. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The MREC motif may be critical for tubulin autoregulation.

Miscellaneous. This tubulin does not have a C-terminal tyrosine; however, its C-terminal phenylalanine residue can be cleaved.

Similarity. Belongs to the tubulin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NY65-1	1	yes
Q9NY65-2	2

RefSeq proteins (2): NP_001180343, NP_061816* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000217	Tubulin	Family
IPR002452	Alpha_tubulin	Family
IPR003008	Tubulin_FtsZ_GTPase	Domain
IPR008280	Tub_FtsZ_C	Homologous_superfamily
IPR017975	Tubulin_CS	Conserved_site
IPR018316	Tubulin/FtsZ_2-layer-sand-dom	Domain
IPR023123	Tubulin_C	Homologous_superfamily
IPR036525	Tubulin/FtsZ_GTPase_sf	Homologous_superfamily
IPR037103	Tubulin/FtsZ-like_C	Homologous_superfamily

Pfam: PF00091, PF03953

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (22 total): binding site 9, sequence variant 8, chain 2, splice variant 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY65-F1	91.24	0.80

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 (1): 254

Ligand- & substrate-binding residues (9): 179; 206; 228; 11; 71; 71; 140; 144; 145

Function

Pathways and Gene Ontology

Reactome pathways

82 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-190840	Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
R-HSA-190861	Gap junction assembly
R-HSA-2132295	MHC class II antigen presentation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-389960	Formation of tubulin folding intermediates by CCT/TriC
R-HSA-389977	Post-chaperonin tubulin folding pathway
R-HSA-437239	Recycling pathway of L1
R-HSA-5620920	Cargo trafficking to the periciliary membrane
R-HSA-5626467	RHO GTPases activate IQGAPs
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-68877	Mitotic Prometaphase
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint
R-HSA-8955332	Carboxyterminal post-translational modifications of tubulin
R-HSA-9609690	HCMV Early Events
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9619483	Activation of AMPK downstream of NMDARs
R-HSA-9646399	Aggrephagy
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III
R-HSA-983189	Kinesins
R-HSA-9833482	PKR-mediated signaling
R-HSA-5617833	Cilium Assembly
R-HSA-109582	Hemostasis

MSigDB gene sets: 262 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, WHITEHURST_PACLITAXEL_SENSITIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_MALE_GAMETE_GENERATION, REACTOME_MEMBRANE_TRAFFICKING, CAGCTG_AP4_Q5, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM

GO Biological Process (6): microtubule cytoskeleton organization (GO:0000226), mitotic cell cycle (GO:0000278), spermatid development (GO:0007286), cytoskeleton organization (GO:0007010), microtubule-based process (GO:0007017), spermatogenesis (GO:0007283)

GO Molecular Function (6): structural constituent of cytoskeleton (GO:0005200), GTP binding (GO:0005525), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (6): acrosomal vesicle (GO:0001669), cytoplasm (GO:0005737), microtubule (GO:0005874), microtubule cytoskeleton (GO:0015630), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Mitotic Prometaphase	2
RHO GTPase Effectors	2
Golgi-to-ER retrograde transport	2
Membrane Trafficking	1
Transport of connexons to the plasma membrane	1
Gap junction trafficking	1
Adaptive Immune System	1
Mitotic Anaphase	1
Cellular responses to stress	1
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1
Protein folding	1
L1CAM interactions	1
Assembly of the 9+0 primary cilium	1
ER to Golgi Anterograde Transport	1
M Phase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton organization	2
cytoskeleton	2
cellular anatomical structure	2
microtubule-based process	1
cell cycle	1
mitotic nuclear division	1
germ cell development	1
spermatid differentiation	1
organelle organization	1
cellular process	1
developmental process involved in reproduction	1
male gamete generation	1
structural molecule activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
secretory granule	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4080 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUBA8	TUBB2A	Q13885	915
TUBA8	TUBB	P05218	886
TUBA8	TUBB6	Q9BUF5	812
TUBA8	TUBB4A	P04350	809
TUBA8	TUBB1	Q9H4B7	807
TUBA8	TUBB2B	Q9BVA1	807
TUBA8	TUBB8	Q3ZCM7	807
TUBA8	TUBB4B	P05217	806
TUBA8	TUBB3	Q13509	805
TUBA8	ROBO3	Q96MS0	764
TUBA8	HTATIP2	Q9BUP3	714
TUBA8	TUBGCP3	Q96CW5	558
TUBA8	CCT6B	Q92526	511
TUBA8	HDAC6	Q9UBN7	504
TUBA8	MAPT	P10636	478

IntAct

83 interactions, top by confidence:

A	B	Type	Score
RPLP0	CCNDBP1	psi-mi:“MI:0914”(association)	0.800
CCNDBP1	RPLP0	psi-mi:“MI:0914”(association)	0.800
ERLIN2	ERLIN1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
NOL12	RRP8	psi-mi:“MI:0914”(association)	0.640
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
TCP11L2	TUBA8	psi-mi:“MI:0915”(physical association)	0.560
RPL28	MAGEB2	psi-mi:“MI:0914”(association)	0.560
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
RPL37A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
MACROH2A2	PPM1G	psi-mi:“MI:0914”(association)	0.530
MAK16	NVL	psi-mi:“MI:0914”(association)	0.530
IGHMBP2	THAP12	psi-mi:“MI:0914”(association)	0.530
TRMT10B	MRPS14	psi-mi:“MI:0914”(association)	0.530
ZC3H8	RSL1D1	psi-mi:“MI:0914”(association)	0.530
SV2A	EXTL3	psi-mi:“MI:0914”(association)	0.530
CLIP1	TUBA8	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (302): EHHADH (Two-hybrid), EHHADH (Two-hybrid), TUBA8 (Affinity Capture-MS), EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), EHHADH (Two-hybrid), MID1 (Two-hybrid), TRIM27 (Two-hybrid), TPP2 (Two-hybrid), TRAF1 (Two-hybrid), BHLHE40 (Two-hybrid), SSNA1 (Two-hybrid), PNMA1 (Two-hybrid), TNIP1 (Two-hybrid)

ESM2 similar proteins: A6NHL2, B9DGT7, O22347, O22349, O94128, P06604, P08070, P11139, P11237, P11480, P14640, P14641, P14642, P22275, P28287, P28752, P30436, P33627, P33629, P38669, P50719, P52274, P53372, P68366, P68367, P68368, P81948, P91910, Q02245, Q06331, Q0WV25, Q25008, Q25563, Q2HJB8, Q38771, Q3UX10, Q43473, Q52PV9, Q5I2J3, Q5XIF6

Diamond homologs: A5A6J1, B9DGT7, B9DHQ0, O22347, P02550, P02552, P04106, P05213, P05214, P06603, P06604, P06605, P08537, P09204, P09205, P09243, P09644, P0DPH7, P0DPH8, P10872, P10873, P11237, P11480, P11481, P14640, P14641, P14642, P18258, P18288, P28268, P28287, P29511, P30436, P33623, P33625, P33629, P34690, P36220, P41351, P41383

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NUMA1	up-regulates	TUBA8	binding
TTL	down-regulates	TUBA8	tyrosination
“Elongator complex”	“up-regulates activity”	TUBA8	acetylation
TUBA8	up-regulates	Neuron_migration
ATAT1	“up-regulates quantity by stabilization”	TUBA8	acetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Peptide chain elongation	9	17.6×	9e-08
Viral mRNA Translation	9	17.6×	9e-08
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	9	17.4×	9e-08
Formation of a pool of free 40S subunits	10	17.2×	6e-08
Selenocysteine synthesis	9	16.6×	1e-07
Eukaryotic Translation Termination	9	16.6×	1e-07
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	10	16.4×	6e-08
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	9	16.3×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	9	18.3×	8e-07
translation	10	11.3×	5e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	212
Likely benign	130
Benign	19

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1686847	NM_018943.3(TUBA8):c.59G>A (p.Cys20Tyr)	Pathogenic

SpliceAI

786 predictions. Top by Δscore:

Variant	Effect	Δscore
22:18121476:C:G	acceptor_gain	1.0000
22:18121477:A:AG	acceptor_gain	1.0000
22:18121477:AGC:A	acceptor_gain	1.0000
22:18121477:AGCG:A	acceptor_gain	1.0000
22:18121477:AGCGG:A	acceptor_gain	1.0000
22:18121478:G:GG	acceptor_gain	1.0000
22:18121478:GC:G	acceptor_gain	1.0000
22:18121478:GCG:G	acceptor_gain	1.0000
22:18121478:GCGG:G	acceptor_gain	1.0000
22:18121478:GCGGG:G	acceptor_gain	1.0000
22:18121652:G:GT	donor_gain	1.0000
22:18121652:G:T	donor_gain	1.0000
22:18121697:AGTGG:A	donor_loss	1.0000
22:18121698:GTGG:G	donor_gain	1.0000
22:18121699:TGGG:T	donor_loss	1.0000
22:18121700:GG:G	donor_gain	1.0000
22:18121701:GG:G	donor_gain	1.0000
22:18121702:GTG:G	donor_loss	1.0000
22:18121703:T:A	donor_loss	1.0000
22:18124150:T:A	acceptor_gain	1.0000
22:18124151:G:A	acceptor_gain	1.0000
22:18124151:GGAA:G	acceptor_loss	1.0000
22:18124154:A:AG	acceptor_gain	1.0000
22:18124155:G:GG	acceptor_gain	1.0000
22:18124155:GAT:G	acceptor_gain	1.0000
22:18124155:GATGA:G	acceptor_gain	1.0000
22:18124298:G:GT	donor_gain	1.0000
22:18124300:AGCTG:A	donor_gain	1.0000
22:18124301:GCTG:G	donor_gain	1.0000
22:18124301:GCTGG:G	donor_gain	1.0000

AlphaMissense

2968 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:18126421:G:A	G148D	1.000
22:18126536:C:A	N186K	1.000
22:18126536:C:G	N186K	1.000
22:18126591:G:C	D205H	1.000
22:18126592:A:T	D205V	1.000
22:18126596:C:A	N206K	1.000
22:18126596:C:G	N206K	1.000
22:18126705:C:A	R243S	1.000
22:18126708:T:C	F244L	1.000
22:18126710:T:A	F244L	1.000
22:18126710:T:G	F244L	1.000
22:18126714:G:T	G246W	1.000
22:18126715:G:A	G246E	1.000
22:18126752:C:A	N258K	1.000
22:18126752:C:G	N258K	1.000
22:18126754:T:C	L259P	1.000
22:18126757:T:A	V260E	1.000
22:18126919:C:A	A314D	1.000
22:18126926:C:G	C316W	1.000
22:18126937:G:C	R320P	1.000
22:18126939:G:C	G321R	1.000
22:18126939:G:T	G321C	1.000
22:18126940:G:A	G321D	1.000
22:18126940:G:T	G321V	1.000
22:18127014:T:A	W346R	1.000
22:18127014:T:C	W346R	1.000
22:18127016:G:C	W346C	1.000
22:18127016:G:T	W346C	1.000
22:18127027:G:A	G350D	1.000
22:18127030:T:C	F351S	1.000

dbSNP variants (sampled 300 via entrez): RS1000112177 (22:18110191 C>T), RS1000374101 (22:18120678 G>C), RS1000387942 (22:18131761 G>A), RS1000440375 (22:18131404 T>C,G), RS1001117155 (22:18120202 C>T), RS1001148057 (22:18119984 G>A), RS1001162366 (22:18111012 G>A,T), RS1001257828 (22:18116680 C>A,G,T), RS1001390552 (22:18130418 T>C), RS1001450094 (22:18114349 G>T), RS1001510541 (22:18111175 C>T), RS1001539765 (22:18127548 C>T), RS1001784159 (22:18117724 G>A), RS1001813553 (22:18117573 A>G), RS1002119669 (22:18118957 A>G)

Disease associations

OMIM: gene MIM:605742 | disease phenotypes: MIM:613180, MIM:619840, MIM:126800

GenCC curated gene-disease

Disease	Classification	Inheritance
macrothrombocytopenia, isolated, 2, autosomal dominant	Moderate	Autosomal dominant
polymicrogyria with optic nerve hypoplasia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
polymicrogyria with optic nerve hypoplasia	Disputed	AR

Mondo (4): polymicrogyria with optic nerve hypoplasia (MONDO:0013172), macrothrombocytopenia, isolated, 2, autosomal dominant (MONDO:0030827), Duane retraction syndrome (MONDO:0007473), microcephaly (MONDO:0001149)

Orphanet (2): Polymicrogyria with optic nerve hypoplasia (Orphanet:250972), Duane retraction syndrome (Orphanet:233)

HPO phenotypes

24 total (25 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000421	Epistaxis
HP:0000609	Optic nerve hypoplasia
HP:0000707	Abnormality of the nervous system
HP:0000978	Bruising susceptibility
HP:0001250	Seizure
HP:0001265	Hyporeflexia
HP:0001274	Agenesis of corpus callosum
HP:0001319	Neonatal hypotonia
HP:0001344	Absent speech
HP:0001873	Thrombocytopenia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002126	Polymicrogyria
HP:0002365	Hypoplasia of the brainstem
HP:0004846	Prolonged bleeding after surgery
HP:0006298	Prolonged bleeding after dental extraction
HP:0006989	Dysplastic corpus callosum
HP:0011344	Severe global developmental delay
HP:0011877	Increased mean platelet volume
HP:0012469	Infantile spasms
HP:0030048	Colpocephaly
HP:0032438	Platelet anisocytosis
HP:0040185	Macrothrombocytopenia
HP:0100608	Metrorrhagia
HP:0000252	Microcephaly

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004071_19	Cerebrospinal T-tau levels	7.000000e-06
GCST006061_79	Atrial fibrillation	2.000000e-11
GCST006061_80	Atrial fibrillation	2.000000e-11
GCST006414_41	Atrial fibrillation	2.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004760	t-tau measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004370	Duane Retraction Syndrome	C10.292.562.700.375.500; C11.270.235; C11.590.436.400.500; C16.320.290.235
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567715	Polymicrogyria With Optic Nerve Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3714503 (SINGLE PROTEIN), CHEMBL3832941 (PROTEIN FAMILY), CHEMBL6067579 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.58	IC50	26	nM	PIRONETIN
6.27	IC50	540	nM	CHEMBL4584084
5.32	Kd	4818	nM	CHEMBL5653589
5.32	ED50	4818	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 116 total; 3 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
(2R,3R)-3-ethyl-2-[(E,2R,3S,4R,5S)-2-hydroxy-4-methoxy-3,5-dimethylnon-7-enyl]-2,3-dihydropyran-6-one	1572465: Inhibition of tubulin alpha in human A2780 cells assessed as reduction in cell growth	ic50	0.0260	uM
(2R,3R)-3-ethyl-2-[(2R,3S,4R,5S)-2-hydroxy-4-methoxy-3,5-dimethyl-6-[(2S,3S)-3-methyloxiran-2-yl]hexyl]-2,3-dihydropyran-6-one	1572465: Inhibition of tubulin alpha in human A2780 cells assessed as reduction in cell growth	ic50	0.5400	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149677: Binding affinity to human TUBA8 incubated for 45 mins by Kinobead based pull down assay	kd	4.8181	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases reaction, decreases expression, affects cotreatment, increases expression, affects binding	3
Benzo(a)pyrene	decreases expression, decreases methylation	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
perfluorooctane sulfonic acid	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bromovanin	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	decreases expression	1
Cocaine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Fluorouracil	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1

ChEMBL screening assays

73 unique, capped per target: 72 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3803737	Binding	Binding affinity to TUBA8 in HEK293 proteomes assessed as spectral count ratio at 20 uM incubated for 16 hrs by TAMRA biotin-azide dye based LC-MS/MS analysis relative to control	Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300. — ACS Med Chem Lett
CHEMBL3803220	Functional	Induction of phenotypic perturbation in human ONS cells assessed as increase in apha tubulin marker at 10 uM after 24 hrs by alpha tubulin staining based assay relative to control	A Grand Challenge: Unbiased Phenotypic Function of Metabolites from Jaspis splendens against Parkinson’s Disease. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.