GCN1

Summary

GCN1 (GCN1 activator of EIF2AK4, HGNC:4199) is a protein-coding gene on chromosome 12q24.23, encoding Stalled ribosome sensor GCN1 (Q92616). Ribosome collision sensor that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes. It is a selective cancer dependency (DepMap: 51.1% of cell lines).

Enables several functions, including protein kinase regulator activity; stalled ribosome sensor activity; and ubiquitin-protein transferase regulator activity. Involved in protein-RNA covalent cross-linking repair. Located in cytosol. Is active in cytosolic ribosome.

Source: NCBI Gene 10985 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 413 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 51.1% of screened cell lines
• MANE Select transcript: NM_006836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4199
Approved symbol	GCN1
Name	GCN1 activator of EIF2AK4
Location	12q24.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0219, GCN1L
Ensembl gene	ENSG00000089154
Ensembl biotype	protein_coding
OMIM	605614
Entrez	10985

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 8 retained_intron

ENST00000300648, ENST00000547263, ENST00000547369, ENST00000548132, ENST00000548821, ENST00000549815, ENST00000550471, ENST00000551549, ENST00000551920, ENST00000891846, ENST00000915857, ENST00000915858, ENST00000915859, ENST00000915860, ENST00000915861, ENST00000915862, ENST00000915863, ENST00000915864

RefSeq mRNA: 1 — MANE Select: NM_006836 NM_006836

CCDS: CCDS41847

Canonical transcript exons

ENST00000300648 — 58 exons

Exon	Start	End
ENSE00000564429	120175162	120175212
ENSE00000564432	120174071	120174169
ENSE00000564435	120173653	120173826
ENSE00000564440	120168208	120168300
ENSE00000564449	120163070	120163259
ENSE00000564455	120161880	120162058
ENSE00000564470	120156912	120156992
ENSE00000564476	120155241	120155430
ENSE00000564478	120154970	120155040
ENSE00000564480	120153744	120153909
ENSE00000564500	120144639	120144835
ENSE00000564504	120142824	120142941
ENSE00000564510	120138695	120138856
ENSE00000564518	120137206	120137319
ENSE00000564530	120177447	120177555
ENSE00000755973	120129276	120129494
ENSE00000755977	120130646	120130753
ENSE00000755981	120131926	120132022
ENSE00000755984	120134291	120134405
ENSE00000755985	120134533	120134726
ENSE00000755994	120137545	120137814
ENSE00000755999	120137901	120138044
ENSE00000756009	120140859	120141023
ENSE00000756010	120142507	120142722
ENSE00000756021	120144306	120144448
ENSE00000756029	120144923	120145061
ENSE00000756033	120145262	120145330
ENSE00000756035	120147052	120147272
ENSE00000756040	120148167	120148346
ENSE00000756047	120149606	120149720
ENSE00000756053	120149922	120150043
ENSE00000756055	120151145	120151391
ENSE00000756058	120153213	120153407
ENSE00000756079	120157849	120158030
ENSE00000756089	120162847	120162971
ENSE00000756091	120164336	120164495
ENSE00000756092	120164646	120164721
ENSE00000756094	120170169	120170321
ENSE00000756100	120175746	120175874
ENSE00000756104	120177684	120177752
ENSE00000756106	120178625	120178759
ENSE00000756107	120178852	120178950
ENSE00000756111	120184112	120184243
ENSE00000756116	120184824	120184887
ENSE00000835218	120190298	120190400
ENSE00000835219	120183569	120183677
ENSE00000835222	120131185	120131333
ENSE00001260563	120194680	120194715
ENSE00001426570	120127202	120127974
ENSE00003496145	120138323	120138415
ENSE00003508948	120159825	120160023
ENSE00003518583	120161490	120161583
ENSE00003554615	120158460	120158615
ENSE00003601502	120160142	120160255
ENSE00003605313	120156461	120156604
ENSE00003610577	120176143	120176217
ENSE00003628292	120155592	120155719
ENSE00003656196	120136502	120136732

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 94.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3549 / max 213.2636, expressed in 1803 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133593	26.6515	1801
133595	0.3902	216
133594	0.3132	141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	94.28	gold quality
tendon of biceps brachii	UBERON:0008188	94.11	gold quality
sural nerve	UBERON:0015488	94.02	gold quality
pylorus	UBERON:0001166	93.86	gold quality
adrenal tissue	UBERON:0018303	93.32	gold quality
gastrocnemius	UBERON:0001388	93.20	gold quality
cardia of stomach	UBERON:0001162	92.86	gold quality
muscle of leg	UBERON:0001383	92.84	gold quality
stromal cell of endometrium	CL:0002255	92.50	gold quality
right lobe of thyroid gland	UBERON:0001119	92.29	gold quality
muscle organ	UBERON:0001630	92.26	gold quality
skeletal muscle organ	UBERON:0014892	92.26	gold quality
nipple	UBERON:0002030	92.25	gold quality
granulocyte	CL:0000094	92.21	gold quality
left lobe of thyroid gland	UBERON:0001120	92.20	gold quality
pituitary gland	UBERON:0000007	92.16	gold quality
tonsil	UBERON:0002372	92.15	gold quality
thyroid gland	UBERON:0002046	92.06	gold quality
saphenous vein	UBERON:0007318	91.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.93	gold quality
stomach	UBERON:0000945	91.90	gold quality
renal medulla	UBERON:0000362	91.89	gold quality
pharyngeal mucosa	UBERON:0000355	91.78	gold quality
mucosa of urinary bladder	UBERON:0001259	91.72	gold quality
body of pancreas	UBERON:0001150	91.65	gold quality
body of stomach	UBERON:0001161	91.58	gold quality
body of uterus	UBERON:0009853	91.52	gold quality
skeletal muscle tissue	UBERON:0001134	91.44	gold quality
ganglionic eminence	UBERON:0004023	91.42	gold quality
skin of leg	UBERON:0001511	91.36	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

53 targeting GCN1, 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-3646	100.00	73.56	5283
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-4506	99.34	67.47	526

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 51.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• These findings suggest that GCN1 can regulate eIF2alpha phosphorylation in HSV-1-infected cells and that the GCN1-binding viral partner simplexvirus gH is necessary and sufficient to prevent the accumulation of phosphorylated eIF2alpha. (PMID:25808324)
• The genomic and clinical landscape of fetal akinesia. (PMID:31680123)
• An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes. (PMID:36638793)
• Emerging Role of GCN1 in Disease and Homeostasis. (PMID:38474243)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gcn1	ENSDARG00000058419
mus_musculus	Gcn1	ENSMUSG00000041638
rattus_norvegicus	Gcn1	ENSRNOG00000021871
drosophila_melanogaster	l(3)80Fj	FBGN0287182
caenorhabditis_elegans		WBGENE00021697

Paralogs (1): ECPAS (ENSG00000136813)

Protein

Protein identifiers

Stalled ribosome sensor GCN1 — Q92616 (reviewed: Q92616)

Alternative names: GCN1 eIF-2-alpha kinase activator homolog, GCN1-like protein 1, General control of amino-acid synthesis 1-like protein 1, Translational activator GCN1

All UniProt accessions (1): Q92616

UniProt curated annotations — full annotation on UniProt →

Function. Ribosome collision sensor that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of translation factors on stalled ribosomes. Directly binds to the ribosome and acts as a sentinel for colliding ribosomes: activated following ribosome stalling and promotes recruitment of RNF14, which directly ubiquitinates EEF1A1/eEF1A, leading to its degradation. In addition to EEF1A1/eEF1A, the RNF14-RNF25 translation quality control pathway mediates degradation of ETF1/eRF1 and ubiquitination of ribosomal protein. GCN1 also acts as a positive activator of the integrated stress response (ISR) by mediating activation of EIF2AK4/GCN2 in response to amino acid starvation. Interaction with EIF2AK4/GCN2 on translating ribosomes stimulates EIF2AK4/GCN2 kinase activity, leading to phosphorylation of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1). EIF2S1/eIF-2-alpha phosphorylation converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion.

Subunit / interactions. Interacts with EIF2AK4/GCN2; this interaction stimulates the EIF2AK4/GCN2 kinase activity and is impaired by IMPACT upon a variety of stress conditions, such as amino acid depletion, UV-C irradiation, proteasome inhibitor treatment and glucose deprivation. Interacts with IMPACT; this prevents the interaction of GCN1 with EIF2AK4/GCN2 and inhibits EIF2AK4/GCN2 kinase activity. Interacts with RNF14; interaction takes place following ribosome stalling and promotes recruitment of RNF14.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitously expressed. Expressed in skeletal muscules, ovary and testis.

Domain organisation. The RWDBD (RWD-binding domain) region mediates binding to RWD domain-containing proteins, such as EIF2AK4/GCN2, IMPACT and RNF14.

Similarity. Belongs to the GCN1 family.

RefSeq proteins (1): NP_006827* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021133	HEAT_type_2	Repeat
IPR034085	TOG	Domain
IPR056810	GNC1-like_N	Domain
IPR057546	HEAT_GCN1	Domain

Pfam: PF23271, PF24984, PF24987, PF24993, PF25801

UniProt features (65 total): repeat 47, sequence conflict 8, modified residue 4, initiator methionine 1, chain 1, region of interest 1, coiled-coil region 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92616-F1	82.45	0.15

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): 2, 729, 786, 2276

Mutagenesis-validated functional residues (1):

Position	Phenotype
2312	abolished interaction with rnf14 and decreased interaction with eif2ak4/gcn2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency

MSigDB gene sets: 140 (showing top): MITSIADES_RESPONSE_TO_APLIDIN_DN, MORF_HDAC2, GOBP_TRANSLATION, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOBP_TRANSLATIONAL_ELONGATION, GOBP_CELLULAR_RESPONSE_TO_STARVATION, GOMF_TRANSLATION_FACTOR_ACTIVITY_RNA_BINDING, HAN_SATB1_TARGETS_DN, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GOBP_RESPONSE_TO_STARVATION, GOBP_ORGANELLE_DISASSEMBLY, BOYLAN_MULTIPLE_MYELOMA_C_D_UP, GOCC_RIBOSOME

GO Biological Process (8): regulation of translation (GO:0006417), cellular response to amino acid starvation (GO:0034198), rescue of stalled cytosolic ribosome (GO:0072344), GCN2-mediated signaling (GO:0140469), protein-RNA covalent cross-linking repair (GO:0160127), translational elongation (GO:0006414), ubiquitin-dependent protein catabolic process (GO:0006511), protein K6-linked ubiquitination (GO:0085020)

GO Molecular Function (8): RNA binding (GO:0003723), translation factor activity, RNA binding (GO:0008135), protein kinase regulator activity (GO:0019887), protein serine/threonine kinase activator activity (GO:0043539), cadherin binding (GO:0045296), molecular adaptor activity (GO:0060090), stalled ribosome sensor activity (GO:0170011), ubiquitin-protein transferase regulator activity (GO:0055106)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), ribosome (GO:0005840), membrane (GO:0016020), cytosolic ribosome (GO:0022626)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	3
cellular anatomical structure	3
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cellular response to starvation	1
response to amino acid starvation	1
cytoplasmic translational elongation	1
ribosome disassembly	1
integrated stress response signaling	1
rescue of stalled cytosolic ribosome	1
macromolecule biosynthetic process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein polyubiquitination	1
nucleic acid binding	1
RNA binding	1
translation factor activity	1
protein kinase activity	1
kinase regulator activity	1
protein kinase binding	1
protein serine/threonine kinase activity	1
protein kinase activator activity	1
cell adhesion molecule binding	1
molecular_function	1
binding	1
ribosome binding	1
molecular sensor activity	1
ubiquitin-protein transferase activity	1
enzyme regulator activity	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
cytosol	1
ribosome	1

Protein interactions and networks

STRING

3235 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCN1	EIF2AK4	Q9P2K8	988
GCN1	ABCF3	Q9NUQ8	782
GCN1	EIF2S1	P05198	710
GCN1	HARS1	P12081	689
GCN1	HARS2	P49590	676
GCN1	DRG2	P55039	615
GCN1	ZNF598	Q86UK7	590
GCN1	IMPACT	Q9P2X3	535
GCN1	ASCC3	Q8N3C0	521
GCN1	EEF1A1	P04719	508
GCN1	PRKDC	P78527	507
GCN1	ABCB5	Q2M3G0	493
GCN1	RWDD1	Q9H446	490
GCN1	MCCC2	Q9HCC0	481
GCN1	MED1	Q15648	478

IntAct

230 interactions, top by confidence:

A	B	Type	Score
CHUK	IKBKB	psi-mi:“MI:0914”(association)	0.960
NRAS	RAF1	psi-mi:“MI:0914”(association)	0.930
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
Haus4	HAUS5	psi-mi:“MI:0915”(physical association)	0.560
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
ARLN	DEGS1	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
CD274	TTI1	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
CD40	EXOC5	psi-mi:“MI:0914”(association)	0.530
NPTN	TNPO2	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Tuba3a	PFDN1	psi-mi:“MI:0914”(association)	0.350
Kctd5		psi-mi:“MI:0914”(association)	0.350
Kcnk1	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
NCBP1	TRRAP	psi-mi:“MI:0914”(association)	0.350

BioGRID (454): GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), COPA (Co-fractionation), DNMT1 (Co-fractionation)

ESM2 similar proteins: A0JP94, A1A5F2, A1EC95, A2BID5, A9JRI0, E7FAW3, E7FBU4, E9PVA8, F4HRS2, F4IP13, K8ERU3, O35095, O43299, P42695, P49815, P49816, Q08CY4, Q0DJS1, Q28205, Q2KJ97, Q3U829, Q3UHQ6, Q5JWR5, Q5PRF0, Q5R5R2, Q5SPP5, Q5ZIG0, Q61037, Q640K1, Q642P2, Q68F70, Q6AI08, Q6GN08, Q6GPP1, Q6P1G0, Q6ZNJ1, Q6ZQA0, Q6ZQK0, Q7T006, Q7ZY56

Diamond homologs: A0A0D1CLQ4, A0A0G2K1Q8, A0A139AVY4, A0QFE1, A1AC19, A1B9K8, C5E4D9, D0MYB4, E9PVA8, F4I893, J9VQZ9, O14134, O52618, O59479, O93796, O94489, P08720, P0A9R7, P0A9R8, P0A9R9, P0A9S0, P0A9X1, P0A9X2, P0A9X3, P14175, P16521, P17328, P23703, P25997, P26050, P29551, P53978, P91660, Q08972, Q0T3U8, Q0TGX4, Q0TMS8, Q13ZJ1, Q160Y9, Q1B8U4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 257 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
TRAF6 mediated NF-kB activation	6	16.6×	2e-04
NOD1/2 Signaling Pathway	7	13.5×	2e-04
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	6	13.0×	6e-04
TAK1-dependent IKK and NF-kappa-B activation	7	12.8×	2e-04
MyD88 cascade initiated on plasma membrane	7	8.7×	1e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	7	8.1×	2e-03
MyD88 dependent cascade initiated on endosome	7	8.1×	2e-03
Toll Like Receptor 10 (TLR10) Cascade	6	7.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	8	13.7×	2e-04
tumor necrosis factor-mediated signaling pathway	7	10.8×	2e-03
positive regulation of canonical NF-kappaB signal transduction	14	4.8×	1e-03
protein phosphorylation	13	4.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	308
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

8535 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120127970:AGGGA:A	acceptor_gain	1.0000
12:120127971:GGGA:G	acceptor_gain	1.0000
12:120127972:GGA:G	acceptor_gain	1.0000
12:120127973:GA:G	acceptor_gain	1.0000
12:120127975:C:CC	acceptor_gain	1.0000
12:120127975:C:T	acceptor_loss	1.0000
12:120127976:T:G	acceptor_loss	1.0000
12:120127977:G:C	acceptor_gain	1.0000
12:120129272:CCA:C	donor_loss	1.0000
12:120129273:CA:C	donor_loss	1.0000
12:120129274:A:AC	donor_loss	1.0000
12:120129302:T:C	donor_gain	1.0000
12:120129357:AT:A	donor_gain	1.0000
12:120129490:AGACA:A	acceptor_gain	1.0000
12:120129491:GACA:G	acceptor_gain	1.0000
12:120129492:ACA:A	acceptor_gain	1.0000
12:120129493:CA:C	acceptor_gain	1.0000
12:120129493:CACTG:C	acceptor_gain	1.0000
12:120129495:C:CC	acceptor_gain	1.0000
12:120129497:G:C	acceptor_gain	1.0000
12:120129497:G:GC	acceptor_gain	1.0000
12:120130641:CTCA:C	donor_loss	1.0000
12:120130642:TCACC:T	donor_loss	1.0000
12:120130643:CA:C	donor_loss	1.0000
12:120130645:C:CG	donor_loss	1.0000
12:120130749:GGGAT:G	acceptor_gain	1.0000
12:120130750:GGAT:G	acceptor_gain	1.0000
12:120130750:GGATC:G	acceptor_loss	1.0000
12:120130751:GAT:G	acceptor_gain	1.0000
12:120130751:GATCT:G	acceptor_loss	1.0000

AlphaMissense

17317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120134692:A:G	L2348P	1.000
12:120134703:G:C	F2344L	1.000
12:120134703:G:T	F2344L	1.000
12:120134705:A:G	F2344L	1.000
12:120136575:C:G	R2312P	1.000
12:120136576:G:T	R2312S	1.000
12:120136578:A:T	I2311N	1.000
12:120136581:A:G	L2310P	1.000
12:120136587:C:T	G2308D	1.000
12:120136588:C:G	G2308R	1.000
12:120136663:C:G	A2283P	1.000
12:120136692:A:G	L2273P	1.000
12:120138381:C:T	G2064D	1.000
12:120138756:A:G	L2032P	1.000
12:120138778:C:G	A2025P	1.000
12:120140893:A:G	L1987P	1.000
12:120140896:C:T	G1986D	1.000
12:120140909:C:G	G1982R	1.000
12:120140913:C:A	R1980S	1.000
12:120140913:C:G	R1980S	1.000
12:120140914:C:A	R1980M	1.000
12:120140914:C:G	R1980T	1.000
12:120140950:A:G	L1968P	1.000
12:120140990:T:C	K1955E	1.000
12:120140998:A:G	L1952P	1.000
12:120142559:A:G	L1926P	1.000
12:120142568:A:G	L1923P	1.000
12:120142580:A:C	L1919W	1.000
12:120142601:A:T	V1912D	1.000
12:120142604:A:T	V1911D	1.000

dbSNP variants (sampled 300 via entrez): RS1000006581 (12:120169455 C>G), RS1000091328 (12:120130028 C>T), RS1000096357 (12:120184303 G>A), RS1000165176 (12:120181696 G>A), RS1000166193 (12:120133177 G>A), RS1000196904 (12:120160748 C>T), RS1000246277 (12:120181552 G>A), RS1000258072 (12:120189323 G>A,C), RS1000263756 (12:120139226 C>T), RS1000314285 (12:120138939 T>C), RS1000341955 (12:120187773 G>C), RS1000348726 (12:120160974 C>T), RS1000416589 (12:120145437 G>C), RS1000442793 (12:120154246 G>A), RS1000487192 (12:120137141 G>A)

Disease associations

OMIM: gene MIM:605614 | disease phenotypes: MIM:617468, MIM:208150

GenCC curated gene-disease

Mondo (2): arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (2): Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_453	Obesity-related traits	4.000000e-06
GCST010989_51	Body size at age 10	1.000000e-08
GCST90000025_1001	Appendicular lean mass	4.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3706558 (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
7.24	Kd	57.89	nM	CHEMBL5653589
7.24	ED50	57.89	nM	CHEMBL5653589
7.07	Kd	84.96	nM	CHEMBL3752910
7.07	ED50	84.96	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 19 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148422: Binding affinity to human GCN1L1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0579	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148422: Binding affinity to human GCN1L1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0850	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects binding	3
bisphenol S	affects expression, increases expression	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
ciglitazone	affects binding, increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects expression	1
Cisplatin	decreases expression	1
Diethylstilbestrol	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Furaldehyde	affects cotreatment, increases expression, decreases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Sodium Chloride	decreases expression, increases expression, affects cotreatment	1

ChEMBL screening assays

12 unique, capped per target: 8 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3630219	Functional	Decrease in GCN1 expression in human U251MG cells at 5 uM for 1 hr by mass spectrometry relative to control	Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma. — J Med Chem
CHEMBL4012588	Binding	Binding affinity to GCN1 protein in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2XK	Abcam HEK293T GCN1 KO	Transformed cell line	Female
CVCL_B5NA	PGPC1_73	Induced pluripotent stem cell	Female
CVCL_SP85	HAP1 GCN1L1 (-) 1	Cancer cell line	Male
CVCL_SP86	HAP1 GCN1L1 (-) 2	Cancer cell line	Male
CVCL_SP87	HAP1 GCN1L1 (-) 3	Cancer cell line	Male
CVCL_SP88	HAP1 GCN1L1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3