CARS1

Summary

CARS1 (cysteinyl-tRNA synthetase 1, HGNC:1493) is a protein-coding gene on chromosome 11p15.4, encoding Cysteine–tRNA ligase, cytoplasmic (P49589). Catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys). It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 833 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly, developmental delay, and brittle hair syndrome (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 213 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 136
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001014437

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1493
Approved symbol	CARS1
Name	cysteinyl-tRNA synthetase 1
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000110619
Ensembl biotype	protein_coding
OMIM	123859
Entrez	833

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 15 protein_coding, 4 retained_intron, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000278224, ENST00000380525, ENST00000397111, ENST00000439280, ENST00000465207, ENST00000465240, ENST00000465331, ENST00000466442, ENST00000470221, ENST00000484484, ENST00000524825, ENST00000526890, ENST00000527330, ENST00000529772, ENST00000531387, ENST00000868849, ENST00000868850, ENST00000868851, ENST00000868852, ENST00000920475, ENST00000920476, ENST00000920477, ENST00000920478, ENST00000962720, ENST00000962721, ENST00000962722

RefSeq mRNA: 9 — MANE Select: NM_001014437 NM_001014437, NM_001194997, NM_001378136, NM_001378137, NM_001378138, NM_001378139, NM_001378140, NM_001751, NM_139273

CCDS: CCDS41600, CCDS41602, CCDS7742, CCDS91411

Canonical transcript exons

ENST00000380525 — 23 exons

Exon	Start	End
ENSE00003469051	3039835	3039931
ENSE00003496649	3038050	3038199
ENSE00003500805	3005366	3005433
ENSE00003502544	3018620	3018749
ENSE00003516061	3017857	3017954
ENSE00003526477	3039194	3039292
ENSE00003547206	3006879	3006959
ENSE00003559791	3012195	3012276
ENSE00003567004	3017106	3017295
ENSE00003588930	3018408	3018511
ENSE00003610658	3047753	3048001
ENSE00003610916	3026676	3026797
ENSE00003612036	3015781	3015849
ENSE00003622647	3028996	3029084
ENSE00003628877	3002541	3002600
ENSE00003633683	3019139	3019267
ENSE00003640798	3029303	3029443
ENSE00003672103	3001970	3002053
ENSE00003694096	3020220	3020332
ENSE00003755415	3042165	3042256
ENSE00003756029	3040896	3040984
ENSE00003804894	3057343	3057423
ENSE00003903942	3000929	3001248

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 95.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.2469 / max 243.7578, expressed in 1819 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118272	38.1715	1818
118271	3.3067	1499
118267	0.4163	174
118269	0.1283	48
118268	0.1269	54
118273	0.0972	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	95.22	gold quality
blood	UBERON:0000178	93.81	gold quality
stromal cell of endometrium	CL:0002255	93.77	gold quality
left lobe of thyroid gland	UBERON:0001120	93.03	gold quality
thyroid gland	UBERON:0002046	92.93	gold quality
granulocyte	CL:0000094	92.89	gold quality
skin of leg	UBERON:0001511	92.55	gold quality
prefrontal cortex	UBERON:0000451	92.53	gold quality
right lobe of thyroid gland	UBERON:0001119	92.42	gold quality
zone of skin	UBERON:0000014	92.40	gold quality
adenohypophysis	UBERON:0002196	92.38	gold quality
hypothalamus	UBERON:0001898	92.32	gold quality
skin of abdomen	UBERON:0001416	92.24	gold quality
body of stomach	UBERON:0001161	92.18	gold quality
tibial nerve	UBERON:0001323	92.10	gold quality
pituitary gland	UBERON:0000007	92.06	gold quality
frontal cortex	UBERON:0001870	92.05	gold quality
mucosa of transverse colon	UBERON:0004991	92.05	gold quality
minor salivary gland	UBERON:0001830	91.99	gold quality
saliva-secreting gland	UBERON:0001044	91.85	gold quality
substantia nigra	UBERON:0002038	91.83	gold quality
primary visual cortex	UBERON:0002436	91.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.69	gold quality
lower esophagus mucosa	UBERON:0035834	91.66	gold quality
cortical plate	UBERON:0005343	91.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.59	gold quality
adipose tissue	UBERON:0001013	91.43	gold quality
bone marrow cell	CL:0002092	91.42	gold quality
right frontal lobe	UBERON:0002810	91.41	gold quality
sural nerve	UBERON:0015488	91.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, CREB1

miRNA regulators (miRDB)

12 targeting CARS1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-943	97.81	64.42	694
HSA-MIR-711	96.60	65.75	528
HSA-MIR-554	95.20	66.98	341

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• CARS is a novel fusion partner of anaplastic lymphoma kinase in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor cases. (PMID:12112524)
• Specificity of anticodon recognition by human CysRS is higher than that of its bacterial counterparts. (PMID:17303165)
• Loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine-glutamate antiporter known as system xc(-). (PMID:26184909)
• The risk (G and C) and non-risk (C and T) allele frequencies of the SNPs at the rs1888747 and rs739401 loci of FRMD3 and CARS, respectively, did not differ significantly between the diabetics with (case) and without (control) nephropathy (P > 0.05). (PMID:26909942)
• Four single nucleotide polymorphisms (SNPs) of CARS were significantly associated with gastric cancer risk in both the discovery stage and the validation stage (PMID:28409418)
• Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. (PMID:30824121)
• Endogenous TLR2 ligand embedded in the catalytic region of human cysteinyl-tRNA synthetase 1. (PMID:32461342)
• CARS senses cysteine deprivation to activate AMPK for cell survival. (PMID:34472622)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cars1	ENSDARG00000036164
mus_musculus	Cars1	ENSMUSG00000010755
rattus_norvegicus	Cars1	ENSRNOG00000020651
drosophila_melanogaster	CysRS	FBGN0027091
caenorhabditis_elegans	cars-1	WBGENE00000800

Paralogs (1): CARS2 (ENSG00000134905)

Protein

Protein identifiers

Cysteine–tRNA ligase, cytoplasmic — P49589 (reviewed: P49589)

Alternative names: Cysteinyl-tRNA synthetase

All UniProt accessions (5): P49589, B4DKY1, C9JLN0, E9PLP0, E9PRS8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys).

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Disease relevance. Microcephaly, developmental delay, and brittle hair syndrome (MDBH) [MIM:618891] An autosomal recessive disorder characterized by developmental delay, motor and cognitive disabilities, brittle hair and nails, failure to thrive, and short stature. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving CARS is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with ALK.

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. Found in 20% of the mRNAs.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P49589-1	1	yes
P49589-2	2
P49589-3	3

RefSeq proteins (9): NP_001014437, NP_001181926, NP_001365065, NP_001365066, NP_001365067, NP_001365068, NP_001365069, NP_001742, NP_644802 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR015803	Cys-tRNA-ligase	Family
IPR024909	Cys-tRNA/MSH_ligase	Family
IPR032678	tRNA-synt_1_cat_dom	Domain

Pfam: PF01406

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Cys) + L-cysteine + ATP = L-cysteinyl-tRNA(Cys) + AMP + diphosphate (RHEA:17773)

UniProt features (29 total): binding site 8, modified residue 7, sequence variant 4, short sequence motif 3, region of interest 2, splice variant 2, initiator methionine 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49589-F1	90.05	0.64

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 (8): 96; 348; 373; 373; 377; 409; 55; 56

Post-translational modifications (7): 2, 19, 305, 307, 503, 746, 79

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-1643685	Disease
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-72766	Translation
R-HSA-9700206	Signaling by ALK in cancer

MSigDB gene sets: 489 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, TSENG_IRS1_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_TRNA_METABOLIC_PROCESS, EFC_Q6, XU_HGF_SIGNALING_NOT_VIA_AKT1_48HR_UP, GOBP_TRANSLATION, MARTINEZ_RB1_TARGETS_UP, GROSS_HYPOXIA_VIA_ELK3_DN, ABE_VEGFA_TARGETS_2HR, OCT1_06, MODULE_110, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P

GO Biological Process (3): cysteinyl-tRNA aminoacylation (GO:0006423), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (10): tRNA binding (GO:0000049), cysteine-tRNA ligase activity (GO:0004817), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
tRNA Aminoacylation	1
Signaling by ALK in cancer	1
Translation	1
Disease	1
Metabolism of proteins	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tRNA aminoacylation for protein translation	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
translation	1
tRNA aminoacylation	1
RNA binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARS1	IARS2	Q9NSE4	889
CARS1	PARS2	Q7L3T8	883
CARS1	IARS1	P41252	882
CARS1	LARS2	Q15031	876
CARS1	LARS1	Q9P2J5	876
CARS1	SARS1	P49591	864
CARS1	M0R2C6	M0R2C6	857
CARS1	SARS2	Q9NP81	857
CARS1	VARS2	Q5ST30	821
CARS1	AARS1	P49588	811
CARS1	VARS1	P26640	811
CARS1	MARS1	P56192	810
CARS1	NARS2	Q96I59	810
CARS1	QARS1	P47897	810
CARS1	YARS2	Q9Y2Z4	806
CARS1	RARS2	Q5T160	806

IntAct

45 interactions, top by confidence:

A	B	Type	Score
EEF1G	EEF1B2	psi-mi:“MI:0914”(association)	0.890
EEF1A2	EEF1B2	psi-mi:“MI:0914”(association)	0.740
MLLT6	RGPD8	psi-mi:“MI:0914”(association)	0.530
EEF1G	INPPL1	psi-mi:“MI:0914”(association)	0.530
EEF1A1	ZPR1	psi-mi:“MI:0914”(association)	0.530
ABTB1	VARS1	psi-mi:“MI:0914”(association)	0.530
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
NS	CARS1	psi-mi:“MI:0915”(physical association)	0.370
CARS1	NS1	psi-mi:“MI:0915”(physical association)	0.370
CARS1	NS	psi-mi:“MI:0915”(physical association)	0.370
GRN	OPA1	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
EEF1D	VWA8	psi-mi:“MI:0914”(association)	0.350
ERP27	EEF1B2	psi-mi:“MI:0914”(association)	0.350
KMT5B	CARS1	psi-mi:“MI:0914”(association)	0.350
EEF1A2	IGLL5	psi-mi:“MI:0914”(association)	0.350
EEF1D	AHCYL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (139): CARS (Reconstituted Complex), CARS (Affinity Capture-MS), CARS (Co-fractionation), CARS (Co-fractionation), CARS (Co-fractionation), CARS (Co-fractionation), CARS (Co-fractionation), LARS (Co-fractionation), MCFD2 (Co-fractionation), PROSC (Co-fractionation), CARS (Affinity Capture-MS), CARS (Affinity Capture-MS), CARS (Affinity Capture-MS), CARS (Affinity Capture-MS), CARS (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6LAG9, A2YQ56, A6H7E1, B3LFA4, B8B4H5, B9FK36, B9FSH5, F4I1L3, F4IPY2, F4KE63, O23247, O24357, O75005, P49589, P49696, P93736, Q0IZQ2, Q2KIF8, Q2QMG2, Q43727, Q43768, Q43794, Q43839, Q499X9, Q4R646, Q5M7N8, Q5ZKA2, Q69UZ3, Q6DJ95, Q6GQJ7, Q6PA41, Q7T0Z0, Q8BIJ6, Q8BYM8, Q8L743, Q8L785, Q8RXE9, Q8RXK8, Q8S6N5, Q90YI3

Diamond homologs: A0LK15, A1TI06, A1VDQ5, A1VEL2, A3DKS1, A3MS54, A4FR54, A4T4R2, A4X9S8, A4XHE2, A5G949, A6UTK3, A7HDA1, A8EXE9, A8F0I8, A8F596, A8GM31, A8GQP6, A8GUK2, B0BW37, B1XND1, B2IEE1, B4UGC3, B5EEK6, B6YST9, B7XHP6, B8DKL0, B8J0S2, B8JDH1, B9LZV4, B9MMM6, C3PMC1, C4K199, C4V8L1, C4XSW5, C5A739, C5BI15, C6BS23, C6E7P0, F4I116

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	CARS1	“transcriptional regulation”
CARS1	“down-regulates quantity”	tRNA(Cys)	“chemical modification”
CARS1	“down-regulates quantity”	cysteine	“chemical modification”
CARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
CARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
CARS1	“up-regulates quantity”	AMP	“chemical modification”
CARS1	“up-regulates quantity”	Cys-tRNA(Cys)	“chemical modification”
CARS1	“up-regulates quantity”	alpha-aminoacyl-tRNA	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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
Eukaryotic Translation Elongation	5	58.0×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	147
Likely benign	27
Benign	9

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2627365	NM_001014437.3(CARS1):c.234_237delinsCAAAGGAGCTTT (p.Ser79fs)	Pathogenic
877075	NM_001014437.3(CARS1):c.2310dup (p.Ser771fs)	Pathogenic
877077	NM_001014437.3(CARS1):c.1387C>T (p.Gln463Ter)	Pathogenic
877078	NM_001014437.3(CARS1):c.1448T>A (p.Leu483Gln)	Pathogenic
877079	NM_001014437.3(CARS1):c.1325C>T (p.Ser442Leu)	Pathogenic
4845877	NM_001014437.3(CARS1):c.367-14C>G	Likely pathogenic
877076	NM_001014437.3(CARS1):c.1271G>A (p.Arg424His)	Likely pathogenic

SpliceAI

4315 predictions. Top by Δscore:

Variant	Effect	Δscore
11:3001960:A:AC	donor_gain	1.0000
11:3001961:C:CC	donor_gain	1.0000
11:3001961:CATG:C	donor_gain	1.0000
11:3001968:A:AC	donor_gain	1.0000
11:3001969:C:CC	donor_gain	1.0000
11:3002536:ATTAC:A	donor_loss	1.0000
11:3002539:A:AC	donor_gain	1.0000
11:3002539:ACTT:A	donor_gain	1.0000
11:3002540:C:CC	donor_gain	1.0000
11:3002540:CTT:C	donor_gain	1.0000
11:3002540:CTTC:C	donor_gain	1.0000
11:3002542:T:TA	donor_gain	1.0000
11:3002599:ACCT:A	acceptor_loss	1.0000
11:3002611:A:T	acceptor_gain	1.0000
11:3005358:TTAC:T	donor_loss	1.0000
11:3005359:TACT:T	donor_loss	1.0000
11:3005360:ACT:A	donor_loss	1.0000
11:3005362:T:TA	donor_loss	1.0000
11:3005363:CACCC:C	donor_loss	1.0000
11:3005364:A:AC	donor_gain	1.0000
11:3005364:A:C	donor_loss	1.0000
11:3005364:AC:A	donor_gain	1.0000
11:3005365:C:CC	donor_gain	1.0000
11:3005365:CC:C	donor_gain	1.0000
11:3005365:CCCGT:C	donor_gain	1.0000
11:3005434:C:CC	acceptor_gain	1.0000
11:3005434:CT:C	acceptor_loss	1.0000
11:3006955:AGGGA:A	acceptor_gain	1.0000
11:3006956:GGGA:G	acceptor_gain	1.0000
11:3006960:C:CC	acceptor_gain	1.0000

AlphaMissense

5503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:3018697:A:G	L400P	1.000
11:3019168:G:C	H373D	1.000
11:3019179:A:G	L369P	1.000
11:3019243:A:G	C348R	1.000
11:3019253:C:A	W344C	1.000
11:3019253:C:G	W344C	1.000
11:3019255:A:G	W344R	1.000
11:3019255:A:T	W344R	1.000
11:3018476:A:G	W438R	0.999
11:3018476:A:T	W438R	0.999
11:3018654:G:C	F414L	0.999
11:3018654:G:T	F414L	0.999
11:3018656:A:G	F414L	0.999
11:3018669:C:A	K409N	0.999
11:3018669:C:G	K409N	0.999
11:3018671:T:C	K409E	0.999
11:3018676:A:G	M407T	0.999
11:3018678:T:A	K406N	0.999
11:3018678:T:G	K406N	0.999
11:3018697:A:T	L400Q	0.999
11:3018714:G:C	F394L	0.999
11:3018714:G:T	F394L	0.999
11:3018716:A:G	F394L	0.999
11:3019154:C:A	E377D	0.999
11:3019154:C:G	E377D	0.999
11:3019163:A:C	H374Q	0.999
11:3019163:A:T	H374Q	0.999
11:3019164:T:G	H374P	0.999
11:3019165:G:C	H374D	0.999
11:3019166:G:C	H373Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000016459 (11:3002247 T>C), RS1000027703 (11:3042574 A>G), RS1000028748 (11:3045809 G>A), RS1000086336 (11:3003474 G>A,C), RS1000095986 (11:3040718 G>A), RS1000105636 (11:3042039 G>C), RS1000111222 (11:3036855 C>A), RS1000185473 (11:3017282 T>C), RS1000200315 (11:3057382 G>A,C,T), RS1000216415 (11:3035591 T>C), RS1000226898 (11:3051907 G>A), RS1000246945 (11:3041898 G>A), RS1000253967 (11:3057510 G>A), RS1000366280 (11:3051051 G>A), RS1000393363 (11:3046813 T>C)

Disease associations

OMIM: gene MIM:123859 | disease phenotypes: MIM:618891

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly, developmental delay, and brittle hair syndrome	Strong	Autosomal recessive

Mondo (1): microcephaly, developmental delay, and brittle hair syndrome (MONDO:0030047)

Orphanet (0):

HPO phenotypes

136 total (30 of 136 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000133	Gonadal dysgenesis
HP:0000176	Submucous cleft hard palate
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000320	Bird-like facies
HP:0000341	Narrow forehead
HP:0000348	High forehead
HP:0000411	Protruding ear
HP:0000460	Narrow nose
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000509	Conjunctivitis
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000565	Esotropia
HP:0000601	Hypotelorism
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000656	Ectropion

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000785_14	Longevity	1.000000e-06
GCST002201_5	Calcium levels	1.000000e-10
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105937 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 13,238 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL2087361	ICOTINIB	3	2,802
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Kd	12	nM	OSIMERTINIB
6.19	Kd	652	nM	ICOTINIB
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 193 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
Osimertinib	1424932: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0120	uM
N-(3-ethynylphenyl)-2,5,8,11-tetraoxa-15,17-diazatricyclo[10.8.0.014,19]icosa-1(12),13,15,17,19-pentaen-18-amine	1424932: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.6520	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178919: Inhibition of CARS (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression, decreases methylation (+1 more)	9
Cyclosporine	affects expression, increases expression	6
sodium arsenite	increases expression	4
Valproic Acid	increases expression, affects expression, decreases expression	4
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases expression	3
Tunicamycin	increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
perfluorooctane sulfonic acid	increases expression	2
entinostat	decreases expression, increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
bisphenol AF	increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cisplatin	decreases expression, increases expression	2
Ethinyl Estradiol	affects expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	increases expression	2
Genistein	affects expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	increases expression	1
sodium arsenate	decreases expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
trichostatin A	decreases expression	1
o,p’-DDT	increases expression	1
sulforaphane	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991645	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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