THG1L

Summary

THG1L (tRNA-histidine guanylyltransferase 1 like, HGNC:26053) is a protein-coding gene on chromosome 5q33.3, encoding Probable tRNA(His) guanylyltransferase (Q9NWX6). Adds a GMP to the 5’-end of tRNA(His) after transcription and RNase P cleavage. It is a selective cancer dependency (DepMap: 80.2% of cell lines).

The protein encoded by this gene is a mitochondrial protein that is induced by high levels of glucose and is associated with diabetic nephropathy. The encoded protein appears to increase mitochondrial biogenesis, which could lead to renal fibrosis. Another function of this protein is that of a guanyltransferase, adding GMP to the 5’ end of tRNA(His). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54974 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 28 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 58 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 15
• Cancer dependency (DepMap): dependent in 80.2% of screened cell lines
• MANE Select transcript: NM_017872

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26053
Approved symbol	THG1L
Name	tRNA-histidine guanylyltransferase 1 like
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	ICF45, FLJ11601, FLJ20546, IHG-1, hTHG1
Ensembl gene	ENSG00000113272
Ensembl biotype	protein_coding
OMIM	618802
Entrez	54974

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 nonsense_mediated_decay

ENST00000231198, ENST00000521655, ENST00000523575, ENST00000884966, ENST00000960053, ENST00000960054

RefSeq mRNA: 4 — MANE Select: NM_017872 NM_001317824, NM_001317825, NM_001317826, NM_017872

CCDS: CCDS4341

Canonical transcript exons

ENST00000231198 — 6 exons

Exon	Start	End
ENSE00001890875	157739321	157741449
ENSE00002205033	157732868	157733044
ENSE00002297776	157731420	157731631
ENSE00002431632	157734576	157734745
ENSE00003564489	157737887	157737994
ENSE00003660766	157735846	157735934

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 87.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6328 / max 110.7990, expressed in 1781 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59837	12.6196	1781
59838	0.0132	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	87.15	gold quality
mononuclear cell	CL:0000842	86.94	gold quality
cartilage tissue	UBERON:0002418	86.83	gold quality
leukocyte	CL:0000738	86.79	gold quality
stromal cell of endometrium	CL:0002255	86.21	gold quality
secondary oocyte	CL:0000655	84.19	gold quality
mucosa of transverse colon	UBERON:0004991	83.78	gold quality
rectum	UBERON:0001052	83.71	gold quality
sperm	CL:0000019	83.06	gold quality
ventricular zone	UBERON:0003053	82.22	gold quality
cortical plate	UBERON:0005343	82.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.60	gold quality
left adrenal gland	UBERON:0001234	81.48	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.40	gold quality
male germ cell	CL:0000015	81.33	gold quality
body of pancreas	UBERON:0001150	81.13	gold quality
right adrenal gland	UBERON:0001233	81.10	gold quality
apex of heart	UBERON:0002098	81.10	gold quality
adrenal tissue	UBERON:0018303	80.93	gold quality
granulocyte	CL:0000094	80.83	gold quality
transverse colon	UBERON:0001157	80.78	gold quality
tendon of biceps brachii	UBERON:0008188	80.77	gold quality
left adrenal gland cortex	UBERON:0035825	80.72	gold quality
islet of Langerhans	UBERON:0000006	80.45	gold quality
right adrenal gland cortex	UBERON:0035827	80.45	gold quality
lower esophagus mucosa	UBERON:0035834	80.44	gold quality
body of stomach	UBERON:0001161	80.33	gold quality
adrenal gland	UBERON:0002369	80.28	gold quality
oocyte	CL:0000023	80.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting THG1L, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-5697	99.39	67.74	1249

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 80.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• ICF45 is a highly conserved novel protein, which is expressed in a cell cycle-dependent manner and seemed to be involved in cell cycle progression and cell proliferation (PMID:15459185)
• induced in high glucose-1 (IHG-1)which increases in diabetic nephropathy, may enhance the actions of TGF-beta1 and contribute to the development of tubulointerstitial fibrosis (PMID:18508967)
• The catalytic domain of Thg1 shares both a common architecture and a two-metal ion-dependent mechanism with canonical 5’-3’ DNA polymerases. (PMID:21078997)
• IHG-1 increases mitochondrial biogenesis by promoting PGC-1alpha-dependent processes, potentially contributing to the pathogenesis of renal fibrosis (PMID:21784897)
• The high-resolution crystal structure of human Thg1 reveals remarkable structural similarity between canonical DNA/RNA polymerases and eukaryotic Thg1. (PMID:22136300)
• IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. Increased IHG-1 expression may contribute to pathogenesis of diabetic kidney disease. (PMID:25008184)
• Study proposes that homozygosity for the p.Val55Ala mutation in tRNA-histidine guanylyltransferase 1 like (THG1L) is the cause of the abnormal mitochondrial network in the patient fibroblasts, likely by interfering with THG1L activity towards MFN2. (PMID:27307223)
• Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population. (PMID:33682303)
• Analysis of GTP addition in the reverse (3’-5’) direction by human tRNA(His) guanylyltransferase. (PMID:33758037)
• Human Thg1 displays tRNA-inducible GTPase activity. (PMID:36107775)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	thg1l	ENSDARG00000038360
mus_musculus	Thg1l	ENSMUSG00000011254
rattus_norvegicus	Thg1l	ENSRNOG00000005539
drosophila_melanogaster	THG	FBGN0283659

Protein

Protein identifiers

Probable tRNA(His) guanylyltransferase — Q9NWX6 (reviewed: Q9NWX6)

Alternative names: Induced in high glucose-1, Interphase cytoplasmic foci protein 45, tRNA-histidine guanylyltransferase

All UniProt accessions (3): Q9NWX6, E5RIQ8, H0YC78

UniProt curated annotations — full annotation on UniProt →

Function. Adds a GMP to the 5’-end of tRNA(His) after transcription and RNase P cleavage. This step is essential for proper recognition of the tRNA and for the fidelity of protein synthesis. Also functions as a guanyl-nucleotide exchange factor/GEF for the MFN1 and MFN2 mitofusins thereby regulating mitochondrial fusion. By regulating both mitochondrial dynamics and bioenergetic function, it contributes to cell survival following oxidative stress.

Subunit / interactions. Homotetramer. Interacts with MFN1 and MFN2; functions as a guanyl-nucleotide exchange factor/GEF for MFN2 and also probably MFN1.

Subcellular location. Cytoplasm. Mitochondrion outer membrane.

Tissue specificity. Expressed in many tissues.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 28 (SCAR28) [MIM:618800] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR28 patients manifest mild motor developmental delay, gait ataxia, and dysarthria. Some patients show mildly impaired intellectual development. Disease onset is in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 magnesium ions per subunit.

Similarity. Belongs to the tRNA(His) guanylyltransferase family.

RefSeq proteins (4): NP_001304753, NP_001304754, NP_001304755, NP_060342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007537	tRNAHis_GuaTrfase_Thg1	Family
IPR024956	tRNAHis_GuaTrfase_cat	Domain
IPR025845	Thg1_C_dom	Domain
IPR038469	tRNAHis_GuaTrfase_Thg1_sf	Homologous_superfamily

Pfam: PF04446, PF14413

Enzyme classification (BRENDA):

• EC 2.7.7.79 — tRNAHis guanylyltransferase (BRENDA: 19 organisms, 53 substrates, 3 inhibitors, 8 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PPP-TRNAHIS	0.0002	2
PPP-TRNAPHE	0.0004–0.025	2
P-TRNAHIS	0.0017	1
PPP-TRNALEU	0.0013	1

Catalyzed reactions (Rhea), 1 shown:

• a 5’-end ribonucleotide-tRNA(His) + GTP + ATP + H2O = a 5’-end phospho-guanosine-ribonucleotide-tRNA(His) + AMP + 2 diphosphate + H(+) (RHEA:54564)

UniProt features (42 total): helix 12, mutagenesis site 9, strand 8, binding site 7, sequence variant 3, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3OTD	X-RAY DIFFRACTION	2.28
3OTE	X-RAY DIFFRACTION	2.56
3OTB	X-RAY DIFFRACTION	2.95
3OTC	X-RAY DIFFRACTION	3.01
7CV1	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWX6-F1	89.84	0.81

Functional residue map

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

Ligand- & substrate-binding residues (7): 58–63; 58; 58; 59; 104–105; 105; 105

Mutagenesis-validated functional residues (9):

Position	Phenotype
58	reduces activity by 99.5%.
63	slightly reduced enzyme activity.
104	slightly reduced enzyme activity.
105	loss of enzyme activity.
106	reduces activity by 95%.
127	abolishes oligomerization. loss of enzyme activity.
181	loss of enzyme activity.
216	reduces activity by 98.5%.
227	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 130 (showing top): GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_MODIFICATION, GOCC_MITOCHONDRIAL_ENVELOPE, ZHAN_MULTIPLE_MYELOMA_HP_UP, GOBP_MITOCHONDRIAL_FUSION, GOBP_PROTEIN_HOMOOLIGOMERIZATION, DOUGLAS_BMI1_TARGETS_UP, GOBP_PROTEIN_TETRAMERIZATION, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOBP_ORGANELLE_FUSION, GOBP_TRNA_MODIFICATION, GOCC_TRANSFERASE_COMPLEX, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY

GO Biological Process (7): tRNA modification (GO:0006400), response to oxidative stress (GO:0006979), tRNA processing (GO:0008033), mitochondrial fusion (GO:0008053), protein homotetramerization (GO:0051289), stress-induced mitochondrial fusion (GO:1990046), tRNA 5’-end processing (GO:0099116)

GO Molecular Function (12): tRNA binding (GO:0000049), magnesium ion binding (GO:0000287), guanyl-nucleotide exchange factor activity (GO:0005085), ATP binding (GO:0005524), GTP binding (GO:0005525), tRNA guanylyltransferase activity (GO:0008193), nucleotidyltransferase activity (GO:0016779), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), transferase complex (GO:1990234), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
tRNA processing	2
purine ribonucleoside triphosphate binding	2
cytoplasm	2
RNA modification	1
response to stress	1
RNA processing	1
tRNA metabolic process	1
mitochondrion organization	1
organelle fusion	1
protein homooligomerization	1
protein tetramerization	1
mitochondrial fusion	1
cellular response to stress	1
RNA 5’-end processing	1
RNA binding	1
metal ion binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
RNA guanylyltransferase activity	1
tRNA 5’-end processing	1
catalytic activity, acting on a tRNA	1
transferase activity, transferring phosphorus-containing groups	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
catalytic complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THG1L	HARS1	P12081	770
THG1L	HARS2	P49590	759
THG1L	TRNT1	Q96Q11	591
THG1L	UBLCP1	Q8WVY7	488
THG1L	TRMT5	Q32P41	464
THG1L	SOX30	O94993	455
THG1L	PDE12	Q6L8Q7	437
THG1L	PUS1	Q9Y606	432
THG1L	ITPA	Q9BY32	430
THG1L	ADAM19	Q9H013	418
THG1L	YARS1	P54577	407
THG1L	NSUN2	Q08J23	403
THG1L	TRMT10C	Q7L0Y3	398
THG1L	TRIT1	Q9H3H1	396
THG1L	QTRT2	Q9H974	394

IntAct

38 interactions, top by confidence:

A	B	Type	Score
THG1L	THG1L	psi-mi:“MI:0915”(physical association)	0.740
THG1L	THG1L	psi-mi:“MI:0407”(direct interaction)	0.740
PACSIN2	COBL	psi-mi:“MI:0914”(association)	0.740
SDCBP	THG1L	psi-mi:“MI:0915”(physical association)	0.560
THG1L	SDCBP	psi-mi:“MI:0915”(physical association)	0.560
SPS1	THG1L	psi-mi:“MI:0915”(physical association)	0.560
THG1L	SPS1	psi-mi:“MI:0915”(physical association)	0.560
PLEKHF2	THG1L	psi-mi:“MI:0915”(physical association)	0.560
LNX1	THG1L	psi-mi:“MI:0915”(physical association)	0.560
NTAQ1	THG1L	psi-mi:“MI:0915”(physical association)	0.560
ZNF524	C1QBP	psi-mi:“MI:0914”(association)	0.530
PACSIN2	COBLL1	psi-mi:“MI:0914”(association)	0.530
THG1L	TERF1	psi-mi:“MI:0915”(physical association)	0.510
ELMOD1	THG1L	psi-mi:“MI:0915”(physical association)	0.370
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SH3BP5L	PPP1R12A	psi-mi:“MI:0914”(association)	0.350
PACSIN2	COBL	psi-mi:“MI:0914”(association)	0.350
CHCHD2	POLRMT	psi-mi:“MI:0914”(association)	0.350
ZNF524	IPO8	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HSPD1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (72): THG1L (Two-hybrid), THG1L (Two-hybrid), THG1L (Affinity Capture-MS), THG1L (Affinity Capture-MS), ELMOD1 (Two-hybrid), THG1L (Two-hybrid), THG1L (Affinity Capture-MS), THG1L (Affinity Capture-MS), THG1L (Affinity Capture-MS), THG1L (Affinity Capture-MS), THG1L (Two-hybrid), THG1L (Proximity Label-MS), THG1L (Proximity Label-MS), THG1L (Proximity Label-MS), THG1L (Proximity Label-MS)

ESM2 similar proteins: A6NC97, A8MVJ9, F4IRQ5, F4ISV6, F4IY62, G5ECQ8, O02849, O15091, O64967, O88806, P10759, P17532, P20717, P23109, P53215, P70708, Q05B50, Q08642, Q0EAB8, Q2HZ26, Q3V1D3, Q4R366, Q54E29, Q5K651, Q5M965, Q6BKD4, Q6CW75, Q6CY84, Q6DDV1, Q6FPX3, Q75DJ3, Q7SDM8, Q86VD1, Q8C5W4, Q8CGU9, Q8CGV2, Q8IVG5, Q8IWU9, Q8L627, Q9CY52

Diamond homologs: F4IRQ5, F4ISV6, P53215, Q05B50, Q54E29, Q5M965, Q6BKD4, Q6CW75, Q6FPX3, Q75DJ3, Q7SDM8, Q9CY52, Q9NWX6, Q9V3N8, Q9Y7T3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	36
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1321961	NM_017872.5(THG1L):c.529C>T (p.Gln177Ter)	Pathogenic
1321970	NM_017872.5(THG1L):c.182A>C (p.Asn61Thr)	Likely pathogenic
4849402	NM_017872.5(THG1L):c.369-2A>G	Likely pathogenic

SpliceAI

1194 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157732861:T:TA	acceptor_gain	1.0000
5:157732863:T:TA	acceptor_gain	1.0000
5:157732863:TGAA:T	acceptor_loss	1.0000
5:157732866:A:AG	acceptor_gain	1.0000
5:157732866:AG:A	acceptor_gain	1.0000
5:157732867:G:GT	acceptor_gain	1.0000
5:157732867:GG:G	acceptor_gain	1.0000
5:157732867:GGT:G	acceptor_gain	1.0000
5:157732867:GGTT:G	acceptor_gain	1.0000
5:157732867:GGTTT:G	acceptor_gain	1.0000
5:157732990:A:G	donor_gain	1.0000
5:157733040:GCCAG:G	donor_gain	1.0000
5:157733045:G:GC	donor_loss	1.0000
5:157733045:G:GG	donor_gain	1.0000
5:157733046:T:G	donor_loss	1.0000
5:157734546:A:AG	acceptor_gain	1.0000
5:157734551:A:AG	acceptor_gain	1.0000
5:157734552:C:G	acceptor_gain	1.0000
5:157734555:A:AG	acceptor_gain	1.0000
5:157734742:GATT:G	donor_gain	1.0000
5:157734744:TT:T	donor_gain	1.0000
5:157734746:G:GG	donor_gain	1.0000
5:157737968:A:T	donor_gain	1.0000
5:157738603:T:A	acceptor_gain	1.0000
5:157739313:A:AG	acceptor_gain	1.0000
5:157739313:ACCT:A	acceptor_gain	1.0000
5:157739314:C:G	acceptor_gain	1.0000
5:157739316:T:A	acceptor_gain	1.0000
5:157739316:TGTAG:T	acceptor_loss	1.0000
5:157739317:GTAGG:G	acceptor_loss	1.0000

AlphaMissense

1993 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:157734734:G:C	R176P	0.996
5:157732986:A:C	S104R	0.995
5:157732988:T:A	S104R	0.995
5:157732988:T:G	S104R	0.995
5:157734730:T:A	W175R	0.995
5:157734730:T:C	W175R	0.995
5:157731624:T:C	F62L	0.994
5:157731626:C:A	F62L	0.994
5:157731626:C:G	F62L	0.994
5:157732934:T:G	C86W	0.994
5:157734673:T:C	F156L	0.994
5:157734675:T:A	F156L	0.994
5:157734675:T:G	F156L	0.994
5:157731616:G:A	G59D	0.993
5:157734674:T:C	F156S	0.993
5:157732981:G:A	G102E	0.992
5:157732998:A:C	S108R	0.992
5:157733000:C:A	S108R	0.992
5:157733000:C:G	S108R	0.992
5:157734680:G:A	G158E	0.992
5:157737971:G:T	G238W	0.992
5:157731543:T:C	F35L	0.991
5:157731545:C:A	F35L	0.991
5:157731545:C:G	F35L	0.991
5:157731613:A:T	D58V	0.991
5:157731614:C:A	D58E	0.991
5:157731614:C:G	D58E	0.991
5:157732993:A:T	E106V	0.991
5:157733036:A:C	R120S	0.991
5:157733036:A:T	R120S	0.991

dbSNP variants (sampled 300 via entrez): RS1000482585 (5:157739009 A>G), RS1001108891 (5:157734191 T>A,C), RS1001544350 (5:157734258 T>C), RS1001598555 (5:157734013 A>G), RS1001756882 (5:157740581 C>T), RS1001940083 (5:157729770 T>C), RS1002099500 (5:157740746 T>C), RS1002126012 (5:157735614 G>A), RS1002306598 (5:157741745 C>G), RS1003216658 (5:157735560 A>G), RS1003317281 (5:157735302 C>T), RS1003350688 (5:157731185 T>C), RS1003777943 (5:157729770 TA>T,TAA), RS1003832718 (5:157741678 T>C), RS1003930419 (5:157734982 G>A,C)

Disease associations

OMIM: gene MIM:618802 | disease phenotypes: MIM:618800

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 28	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 28	Limited	AR

Mondo (2): spinocerebellar ataxia, autosomal recessive 28 (MONDO:0032923), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000648	Optic atrophy
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001320	Cerebellar vermis hypoplasia
HP:0002066	Gait ataxia
HP:0004322	Short stature
HP:0007010	Poor fine motor coordination
HP:0007256	Abnormal pyramidal sign
HP:0007772	Impaired smooth pursuit
HP:0007979	Gaze-evoked horizontal nystagmus
HP:0030147	Truncal titubation

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002404_227	Red cell distribution width	6.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases expression, increases abundance	2
Cyclosporine	increases expression	2
alpha phellandrene	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	affects expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Glucose	increases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice