NARS1

Summary

NARS1 (asparaginyl-tRNA synthetase 1, HGNC:7643) is a protein-coding gene on chromosome 18q21.31, encoding Asparagine–tRNA ligase, cytoplasmic (O43776). Catalyzes the attachment of asparagine to tRNA(Asn) in a two-step reaction: asparagine is first activated by ATP to form Asn-AMP and then transferred to the acceptor end of tRNA(Asn). It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Asparaginyl-tRNA synthetase is localized to the cytoplasm and belongs to the class II family of tRNA synthetases. The N-terminal domain represents the signature sequence for the eukaryotic asparaginyl-tRNA synthetases.

Source: NCBI Gene 4677 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 234 total — 3 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_004539

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7643
Approved symbol	NARS1
Name	asparaginyl-tRNA synthetase 1
Location	18q21.31
Locus type	gene with protein product
Status	Approved
Aliases	AsnRS
Ensembl gene	ENSG00000134440
Ensembl biotype	protein_coding
OMIM	108410
Entrez	4677

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 21 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000256854, ENST00000411676, ENST00000540592, ENST00000586807, ENST00000587194, ENST00000587366, ENST00000587675, ENST00000588661, ENST00000589001, ENST00000589314, ENST00000590123, ENST00000591599, ENST00000902983, ENST00000902984, ENST00000902985, ENST00000902986, ENST00000902987, ENST00000902988, ENST00000902989, ENST00000925914, ENST00000925915, ENST00000925916, ENST00000925917, ENST00000925918, ENST00000944520, ENST00000944521, ENST00000944522, ENST00000944523

RefSeq mRNA: 1 — MANE Select: NM_004539 NM_004539

CCDS: CCDS32837

Canonical transcript exons

ENST00000256854 — 14 exons

Exon	Start	End
ENSE00001225301	57621708	57621836
ENSE00001625791	57600656	57601783
ENSE00003461119	57611637	57611707
ENSE00003461949	57609357	57609443
ENSE00003478089	57605857	57605970
ENSE00003482714	57615817	57615975
ENSE00003509365	57602812	57602943
ENSE00003512665	57602355	57602486
ENSE00003556619	57606616	57606751
ENSE00003567090	57607134	57607333
ENSE00003580355	57613602	57613680
ENSE00003631659	57615641	57615730
ENSE00003642036	57607444	57607665
ENSE00003650295	57620569	57620651

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 140.7118 / max 4276.8406, expressed in 1823 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172113	139.4855	1823
172111	0.6628	293
172112	0.5635	195

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.61	gold quality
pancreatic ductal cell	CL:0002079	99.56	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.52	gold quality
cervix squamous epithelium	UBERON:0006922	99.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.45	gold quality
middle temporal gyrus	UBERON:0002771	99.41	gold quality
epithelial cell of pancreas	CL:0000083	99.36	gold quality
nephron tubule	UBERON:0001231	99.19	gold quality
gingival epithelium	UBERON:0001949	99.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.15	gold quality
parotid gland	UBERON:0001831	99.13	gold quality
colonic mucosa	UBERON:0000317	99.09	gold quality
choroid plexus epithelium	UBERON:0003911	99.08	gold quality
squamous epithelium	UBERON:0006914	99.05	gold quality
CA1 field of hippocampus	UBERON:0003881	99.04	gold quality
renal medulla	UBERON:0000362	98.98	gold quality
substantia nigra pars compacta	UBERON:0001965	98.98	gold quality
kidney epithelium	UBERON:0004819	98.98	gold quality
germinal epithelium of ovary	UBERON:0001304	98.96	gold quality
gingiva	UBERON:0001828	98.93	gold quality
ileal mucosa	UBERON:0000331	98.91	gold quality
bronchial epithelial cell	CL:0002328	98.90	gold quality
pons	UBERON:0000988	98.90	gold quality
esophagus squamous epithelium	UBERON:0006920	98.89	gold quality
epithelium of nasopharynx	UBERON:0001951	98.88	gold quality
nasopharynx	UBERON:0001728	98.86	gold quality
renal glomerulus	UBERON:0000074	98.85	gold quality
nasal cavity epithelium	UBERON:0005384	98.84	gold quality
pigmented layer of retina	UBERON:0001782	98.82	gold quality
metanephric glomerulus	UBERON:0004736	98.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6819	no	1046.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, YY1

miRNA regulators (miRDB)

42 targeting NARS1, 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-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-1261	98.62	68.10	896

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• Study shows that ERO1L and NARS expression level are up-regulated in primary lung adenocarcinoma and identifies them with a potential to promote tumor metastasis and growth of cancer cells. (PMID:27161446)
• The chemokine activity of UNE-N was significantly reduced by suppressing CCR3 expression with CCR3-targeting siRNA, and the loop3 region of UNE-N was shown to interact mainly with the extracellular domains of CCR3 in nuclear magnetic resonance perturbation experiments. Based on these results, evolutionarily acquired UNE-N elicits chemokine activities that would promote NRS-CCR3-mediated proinflammatory signaling in ILD. (PMID:30171954)
• Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. (PMID:32788587)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nars1	ENSDARG00000061100
mus_musculus	Nars1	ENSMUSG00000024587
rattus_norvegicus	Nars1	ENSRNOG00000017852
drosophila_melanogaster	AsnRS	FBGN0086443
caenorhabditis_elegans	nars-1	WBGENE00003815

Paralogs (4): KARS1 (ENSG00000065427), DARS1 (ENSG00000115866), DARS2 (ENSG00000117593), NARS2 (ENSG00000137513)

Protein

Protein identifiers

Asparagine–tRNA ligase, cytoplasmic — O43776 (reviewed: O43776)

Alternative names: Asparaginyl-tRNA synthetase, Asparaginyl-tRNA synthetase 1

All UniProt accessions (7): O43776, K7EIU7, K7EJ19, K7EMQ6, K7ENF0, K7EPK2, K7EQ35

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of asparagine to tRNA(Asn) in a two-step reaction: asparagine is first activated by ATP to form Asn-AMP and then transferred to the acceptor end of tRNA(Asn). In addition to its essential role in protein synthesis, acts as a signaling molecule that induced migration of CCR3-expressing cells. Has an essential role in the development of the cerebral cortex, being required for proper proliferation of radial glial cells.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Disease relevance. Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG) [MIM:619091] An autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent in infancy, moderate to profound intellectual disability, poor or absent speech and language, delayed walking with variable gait abnormalities, and progressive microcephaly. Additional variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) [MIM:619092] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay apparent in infancy, delayed walking, ataxia, spasticity, impaired intellectual development with poor or absent speech and language, progressive microcephaly, and early-onset seizures in most patients. Facial dysmorphism and a demyelinating peripheral neuropathy may also be observed. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal domain (1-77) recruits and activates specific immune cells by interacting with CCR3-expressing cells.

Miscellaneous. Autoantibodies to NARS1, are often detected in sera from patients with interstitial lung disease (ILD).

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43776-1	1	yes
O43776-2	2

RefSeq proteins (1): NP_004530* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002312	Asp/Asn-tRNA-synth_IIb	Family
IPR004364	Aa-tRNA-synt_II	Domain
IPR004365	NA-bd_OB_tRNA	Domain
IPR004522	Asn-tRNA-ligase	Family
IPR006195	aa-tRNA-synth_II	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily
IPR048952	AsnRS_N	Domain

Pfam: PF00152, PF01336, PF20917

Enzyme classification (BRENDA):

• EC 6.1.1.22 — asparagine-tRNA ligase (BRENDA: 20 organisms, 26 substrates, 46 inhibitors, 36 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ASN	0.015–0.77	17
ATP	0.0306–7	11
TRNAASN	0.0001–0.002	3
3-CYANOALANINE	5.8	1
ASPARTATE-3-HYDROXAMATE	0.78	1
ISOASPARAGINE	0.26	1
L-ASPARAGINE	0.04	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Asn) + L-asparagine + ATP = L-asparaginyl-tRNA(Asn) + AMP + diphosphate + H(+) (RHEA:11180)

UniProt features (74 total): strand 23, helix 22, sequence variant 13, turn 4, modified residue 4, region of interest 2, splice variant 2, compositionally biased region 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4ZYA	X-RAY DIFFRACTION	1.65
8TC7	X-RAY DIFFRACTION	1.9
8TC8	X-RAY DIFFRACTION	1.9
8TC9	X-RAY DIFFRACTION	2
8H53	X-RAY DIFFRACTION	2.16
5XIX	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43776-F1	93.96	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.

Post-translational modifications (4): 61, 244, 482, 490

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 279 (showing top): GOBP_AMINO_ACID_ACTIVATION, TSENG_IRS1_TARGETS_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_TRNA_METABOLIC_PROCESS, MORF_HDAC1, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_TRANSLATION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, MORF_CTBP1, GOBP_PALLIUM_DEVELOPMENT, GOBP_HEAD_DEVELOPMENT, BROWN_MYELOID_CELL_DEVELOPMENT_DN, MODULE_110, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS

GO Biological Process (5): tRNA aminoacylation for protein translation (GO:0006418), asparaginyl-tRNA aminoacylation (GO:0006421), cell migration (GO:0016477), cerebral cortex development (GO:0021987), translation (GO:0006412)

GO Molecular Function (9): nucleic acid binding (GO:0003676), asparagine-tRNA ligase activity (GO:0004816), ATP binding (GO:0005524), CCR3 chemokine receptor binding (GO:0031728), protein dimerization activity (GO:0046983), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
cell motility	1
pallium development	1
anatomical structure development	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
CCR chemokine receptor binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

2058 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NARS1	ASNS	P08184	909
NARS1	TARS1	P26639	875
NARS1	TARS3	A2RTX5	873
NARS1	TARS2	Q9BW92	871
NARS1	QARS1	P47897	857
NARS1	EPRS1	P07814	856
NARS1	CNDP2	Q96KP4	846
NARS1	IARS2	Q9NSE4	845
NARS1	EARS2	Q5JPH6	844
NARS1	IARS1	P41252	842
NARS1	YARS1	P54577	841
NARS1	AARS1	P49588	823
NARS1	HARS1	P12081	822
NARS1	WARS2	Q9UGM6	808
NARS1	WARS1	P23381	806

IntAct

87 interactions, top by confidence:

A	B	Type	Score
NARS1	ATXN1	psi-mi:“MI:0915”(physical association)	0.670
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
USP47	DENR	psi-mi:“MI:0914”(association)	0.530
HSD3B2	NARS1	psi-mi:“MI:0914”(association)	0.530
LILRA3	NARS1	psi-mi:“MI:0914”(association)	0.530
PRXL2B	NARS1	psi-mi:“MI:0914”(association)	0.530
DUSP19	NARS1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
CPPED1	NARS1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	NARS1	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
MAPT	POTEF	psi-mi:“MI:0914”(association)	0.350
DDX60	G6PD	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
POC5	DSC2	psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
KLHL20	KRBA1	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
DDX19B	IGLL5	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350

BioGRID (191): NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), NARS (Affinity Capture-MS), IARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation), NARS (Co-fractionation)

ESM2 similar proteins: A0KXL6, A1RK52, A1S684, A4Y6E4, A5IE87, A5UCB9, A6L0U5, A6LIA1, A7GTK8, A9NE58, O43776, O94567, P10723, P15180, P37879, P38707, P43829, Q0HIB6, Q0HUL3, Q15046, Q19722, Q1DA04, Q1MQG9, Q2KJG3, Q2SJV9, Q3IGU4, Q481G3, Q4R4Z1, Q554D9, Q5L8W2, Q5QZ13, Q5WUG0, Q5X300, Q5XIM7, Q633N6, Q6BU46, Q6F0Y5, Q6F2U9, Q6HCW9, Q6MEC9

Diamond homologs: A0RJ11, A0RQ71, A1VZ00, A2RMQ1, A4IQ54, A4VTZ1, A4W083, A5D2C2, A5ISY4, A6QH05, A6U1S3, A7H4H2, A7I058, A7X2E9, A7Z5Y7, A8FL61, A8Z434, A9CTP8, B3PNG8, B4U7P3, B7HE37, B7IIR4, B7JPY8, C1ESU7, C3L608, C3P990, C4V847, C5A4R8, O07683, O43776, O57980, O94567, P10723, P38707, P39772, P41908, P47359, P59517, P67571, P67572

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	NARS1	“transcriptional regulation”
NARS1	“down-regulates quantity”	tRNA(Asn)	“chemical modification”
NARS1	“down-regulates quantity”	asparagine	“chemical modification”
NARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
NARS1	“up-regulates quantity”	Asn-tRNA(Asn)	“chemical modification”
NARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
NARS1	“up-regulates quantity”	AMP	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	15
Uncertain significance	165
Likely benign	22
Benign	2

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
3043011	NM_004539.4(NARS1):c.251_252del (p.Glu84fs)	Pathogenic
977507	NM_004548.3(NDUFB10):c.207dup (p.Glu70Ter)	Pathogenic
986303	NM_004539.4(NARS1):c.203dup (p.Met69fs)	Pathogenic
1077114	NM_004539.4(NARS1):c.965G>T (p.Arg322Leu)	Likely pathogenic
1526421	NM_004539.4(NARS1):c.676G>C (p.Val226Leu)	Likely pathogenic
1526422	NM_004539.4(NARS1):c.986G>A (p.Arg329Gln)	Likely pathogenic
1700234	NM_004539.4(NARS1):c.713G>A (p.Arg238Gln)	Likely pathogenic
1700235	NM_004539.4(NARS1):c.179A>C (p.Lys60Thr)	Likely pathogenic
1879400	NM_004539.4(NARS1):c.421+1G>A	Likely pathogenic
3341007	NM_004539.4(NARS1):c.1319T>C (p.Phe440Ser)	Likely pathogenic
3899253	NM_004539.4(NARS1):c.1022del (p.Glu341fs)	Likely pathogenic
4075439	NM_004539.4(NARS1):c.1315C>T (p.Arg439Ter)	Likely pathogenic
4538542	NM_004539.4(NARS1):c.1460C>T (p.Ala487Val)	Likely pathogenic
4687947	NM_004539.4(NARS1):c.1208A>T (p.His403Leu)	Likely pathogenic
4759249	NM_004539.4(NARS1):c.901C>T (p.Gln301Ter)	Likely pathogenic
4814143	NM_004539.4(NARS1):c.376C>T (p.Gln126Ter)	Likely pathogenic
4845747	NM_004539.4(NARS1):c.277_278del (p.Lys93fs)	Likely pathogenic
986308	NM_004539.4(NARS1):c.50C>T (p.Thr17Met)	Likely pathogenic

SpliceAI

1832 predictions. Top by Δscore:

Variant	Effect	Δscore
18:57601780:TTCT:T	acceptor_gain	1.0000
18:57601782:CT:C	acceptor_gain	1.0000
18:57601784:C:CC	acceptor_gain	1.0000
18:57602352:TACC:T	donor_loss	1.0000
18:57602354:C:CA	donor_loss	1.0000
18:57602396:C:A	donor_gain	1.0000
18:57602485:ACCT:A	acceptor_loss	1.0000
18:57602486:CCTTT:C	acceptor_loss	1.0000
18:57602487:C:A	acceptor_loss	1.0000
18:57602488:T:A	acceptor_loss	1.0000
18:57602493:A:AC	acceptor_gain	1.0000
18:57602493:A:C	acceptor_gain	1.0000
18:57602495:A:AC	acceptor_gain	1.0000
18:57602499:G:C	acceptor_gain	1.0000
18:57602499:G:GC	acceptor_gain	1.0000
18:57602790:A:AC	donor_gain	1.0000
18:57602791:C:CC	donor_gain	1.0000
18:57602791:CT:C	donor_gain	1.0000
18:57602795:TTGAA:T	donor_gain	1.0000
18:57602806:A:C	donor_gain	1.0000
18:57602810:A:AC	donor_gain	1.0000
18:57602811:C:CC	donor_gain	1.0000
18:57602831:T:TA	donor_gain	1.0000
18:57602940:TATC:T	acceptor_gain	1.0000
18:57602942:TC:T	acceptor_gain	1.0000
18:57602943:CC:C	acceptor_gain	1.0000
18:57602944:C:CC	acceptor_gain	1.0000
18:57602944:CTGAG:C	acceptor_loss	1.0000
18:57605852:CATA:C	donor_gain	1.0000
18:57605855:A:AC	donor_gain	1.0000

AlphaMissense

3589 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:57602860:C:A	K445N	1.000
18:57602860:C:G	K445N	1.000
18:57607144:G:C	H331D	1.000
18:57601749:C:T	G517D	0.999
18:57601755:C:T	G515E	0.999
18:57601758:C:T	G514E	0.999
18:57602369:A:G	W501R	0.999
18:57602369:A:T	W501R	0.999
18:57602438:G:T	R478S	0.999
18:57602449:C:T	G474E	0.999
18:57602457:C:A	E471D	0.999
18:57602457:C:G	E471D	0.999
18:57602458:T:A	E471V	0.999
18:57602461:C:T	G470D	0.999
18:57602462:C:G	G470R	0.999
18:57602481:G:C	D463E	0.999
18:57602481:G:T	D463E	0.999
18:57602482:T:A	D463V	0.999
18:57602483:C:G	D463H	0.999
18:57602854:G:C	F447L	0.999
18:57602854:G:T	F447L	0.999
18:57602856:A:G	F447L	0.999
18:57602862:T:C	K445E	0.999
18:57602875:A:C	F440L	0.999
18:57602875:A:T	F440L	0.999
18:57602876:A:C	F440C	0.999
18:57602877:A:G	F440L	0.999
18:57602923:C:A	E424D	0.999
18:57602923:C:G	E424D	0.999
18:57607142:G:C	H331Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000098934 (18:57603897 C>A,G,T), RS1000124297 (18:57618551 G>A), RS1000185149 (18:57622369 C>A,G,T), RS1000211991 (18:57616177 A>T), RS1000302392 (18:57603530 G>GT), RS1000314643 (18:57622051 C>A,G,T), RS1000341961 (18:57609731 GTTTA>G), RS1000512718 (18:57621287 G>A), RS1000631055 (18:57612417 T>C), RS1000707294 (18:57606240 T>A), RS1000823191 (18:57616482 C>T), RS1001097843 (18:57615343 A>C,G,T), RS1001451155 (18:57613294 A>G), RS1001487841 (18:57600703 T>C), RS1001552640 (18:57608508 G>C)

Disease associations

OMIM: gene MIM:108410 | disease phenotypes: MIM:619091, MIM:619092, MIM:619003

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities	Strong	Autosomal recessive
neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities	Moderate	AD
neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities	Moderate	AR

Mondo (4): neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (MONDO:0100348), neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (MONDO:0030837), mitochondrial complex 1 deficiency, nuclear type 35 (MONDO:0033560), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000687	Widely spaced teeth
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0001159	Syndactyly
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001761	Pes cavus
HP:0002066	Gait ataxia
HP:0002079	Hypoplasia of the corpus callosum

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067032 (SINGLE PROTEIN)

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
7.55	Kd	28.36	nM	CHEMBL3752910
7.55	ED50	28.36	nM	CHEMBL3752910
5.25	Kd	5574	nM	CHEMBL5653589
5.25	ED50	5574	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148824: Binding affinity to human NARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0284	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148824: Binding affinity to human NARS incubated for 45 mins by Kinobead based pull down assay	kd	5.5735	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	2
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
perfluorooctane sulfonic acid	increases expression	2
chloropicrin	affects expression, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression, affects cotreatment	2
Hydrogen Peroxide	affects expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, increases expression	1
chloroacetaldehyde	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CD 437	decreases expression	1
enniatins	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases 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
CHEMBL5651866	Binding	Binding affinity to human NARS 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)

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