DCPS

Summary

DCPS (decapping enzyme, scavenger, HGNC:29812) is a protein-coding gene on chromosome 11q24.2, encoding m7GpppX diphosphatase (Q96C86). Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3’->5’ exosome-mediated mRNA decay pathway. It is a selective cancer dependency (DepMap: 18.0% of cell lines).

This gene encodes a member of the histidine triad family of pyrophosphatases that removes short mRNA fragments containing the 5′ mRNA cap structure, which appear in the 3′ → 5′ mRNA decay pathway, following deadenylation and exosome-mediated turnover. This enzyme hydrolyzes the triphosphate linkage of the cap structure (7-methylguanosine nucleoside triphosphate) to yield 7-methylguanosine monophosphate and nucleoside diphosphate. It protects the cell from the potentially toxic accumulation of these short, capped mRNA fragments, and regulates the activity of other cap-binding proteins, which are inhibited by their accumulation. It also acts as a transcript-specific modulator of pre-mRNA splicing and microRNA turnover.

Source: NCBI Gene 28960 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Al-Raqad syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 117 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 18.0% of screened cell lines
• MANE Select transcript: NM_014026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29812
Approved symbol	DCPS
Name	decapping enzyme, scavenger
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC015, HINT-5, HSL1, HINT5, DCS-1, DCS1
Ensembl gene	ENSG00000110063
Ensembl biotype	protein_coding
OMIM	610534
Entrez	28960

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263579, ENST00000529149, ENST00000530860, ENST00000648516, ENST00000861222, ENST00000861223, ENST00000912051, ENST00000912052, ENST00000912053, ENST00000912054, ENST00000912055, ENST00000971356

RefSeq mRNA: 2 — MANE Select: NM_014026 NM_001350236, NM_014026

CCDS: CCDS8473

Canonical transcript exons

ENST00000263579 — 6 exons

Exon	Start	End
ENSE00000749617	126338286	126338399
ENSE00001127770	126306570	126306744
ENSE00001202827	126331405	126331550
ENSE00001324469	126304060	126304281
ENSE00003480718	126345347	126350005
ENSE00003684021	126343307	126343417

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 94.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.7130 / max 173.1503, expressed in 1812 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117497	25.4830	1812
117498	0.2300	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.38	gold quality
liver	UBERON:0002107	90.83	gold quality
metanephros cortex	UBERON:0010533	89.97	gold quality
oocyte	CL:0000023	89.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.91	gold quality
granulocyte	CL:0000094	86.61	gold quality
secondary oocyte	CL:0000655	85.88	gold quality
gall bladder	UBERON:0002110	85.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.66	gold quality
mucosa of transverse colon	UBERON:0004991	83.92	gold quality
stromal cell of endometrium	CL:0002255	83.53	gold quality
spleen	UBERON:0002106	83.37	gold quality
palpebral conjunctiva	UBERON:0001812	83.08	gold quality
leukocyte	CL:0000738	83.00	gold quality
blood	UBERON:0000178	82.74	gold quality
monocyte	CL:0000576	82.73	gold quality
mononuclear cell	CL:0000842	82.69	gold quality
endocervix	UBERON:0000458	82.66	gold quality
adult mammalian kidney	UBERON:0000082	82.46	gold quality
gastrocnemius	UBERON:0001388	82.10	gold quality
muscle of leg	UBERON:0001383	82.08	gold quality
right adrenal gland	UBERON:0001233	81.87	gold quality
bone marrow cell	CL:0002092	81.53	gold quality
left adrenal gland	UBERON:0001234	81.47	gold quality
right adrenal gland cortex	UBERON:0035827	81.21	gold quality
left adrenal gland cortex	UBERON:0035825	81.19	gold quality
pigmented layer of retina	UBERON:0001782	80.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.71	gold quality
ventricular zone	UBERON:0003053	80.54	gold quality
ectocervix	UBERON:0012249	80.03	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): BRD4, JMJD6

miRNA regulators (miRDB)

10 targeting DCPS, 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-153-5P	99.89	73.86	6317
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-432-5P	98.00	68.13	989
HSA-MIR-6500-3P	97.42	67.20	867
HSA-MIR-1270	96.94	66.65	931
HSA-MIR-620	96.94	66.79	888

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• The central histidine within the DcpS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function. (PMID:12198172)
• m7GDP breakdown by DcpS should prevent misincorporation of methylated nucleotides in nucleic acids and could generate a unique indicator allowing the cell to monitor mRNA decay. (PMID:14523240)
• Structural and biochemical analysis suggests an autoregulatory mechanism whereby premature decapping mRNA is prevented by blocking the conformational changes that are required to form a closed productive active site capable of cap hydrolysis. (PMID:15068804)
• crystal structures of DcpS in ligand-free form and in a complex with m7GDP (PMID:15769464)
• Furthermore, we show that a novel human histidine triad protein DCS-1, which is expressed together with NR1 in many tissues, can significantly reduce menadione-induced cytotoxicity in these cells (PMID:16140270)
• These studies demonstrate that the significance of DcpS extends beyond its well-characterized role in mRNA decay and involves a broader range of functions in RNA processing including nuclear pre-mRNA splicing. (PMID:18426921)
• biochemical analysis of the dynamic and mutually exclusive cap hydrolysis activity of the two cap binding sites of DcpS (PMID:18441014)
• Data established that DcpS, a key enzyme in mRNA decay, is a new target of DeltaLf transcriptional activity. (PMID:18725266)
• In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. (PMID:25701870)
• DCPS and more generally RNA catabolism, are critical for neurological development, normal cognition and organismal homeostasis in humans. (PMID:25712129)
• data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript-selective manner in mammalian cells (PMID:26001796)
• In DcpS, conformational change is dominated by an anti-symmetric cooperative motion, causing one active site to close as the other opens; however a symmetric motion is also significant. (PMID:26241964)
• Data show that decapping scavenger enzyme DcpS (DcpS) is a nucleocytoplasmic shuttling protein that activates microRNA (miRNA) degradation. (PMID:26584588)
• Molecular basis of the selective processing of short mRNA substrates by the DcpS mRNA decapping enzyme. (PMID:32723815)
• Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS. (PMID:32770650)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dcps	ENSDARG00000009862
mus_musculus	Dcps	ENSMUSG00000032040
rattus_norvegicus	Dcps	ENSRNOG00000072197
drosophila_melanogaster	Dcps	FBGN0037372
caenorhabditis_elegans		WBGENE00000940

Protein

Protein identifiers

m7GpppX diphosphatase — Q96C86 (reviewed: Q96C86)

Alternative names: DCS-1, Decapping scavenger enzyme, Hint-related 7meGMP-directed hydrolase, Histidine triad nucleotide-binding protein 5, Histidine triad protein member 5, Scavenger mRNA-decapping enzyme DcpS

All UniProt accessions (3): Q96C86, A0A384MTI8, A0A3B3ITF0

UniProt curated annotations — full annotation on UniProt →

Function. Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3’->5’ exosome-mediated mRNA decay pathway. Hydrolyzes cap analog structures like 7-methylguanosine nucleoside triphosphate (m7GpppG) with up to 10 nucleotide substrates (small capped oligoribonucleotides) and specifically releases 5’-phosphorylated RNA fragments and 7-methylguanosine monophosphate (m7GMP). Cleaves cap analog structures like tri-methyl guanosine nucleoside triphosphate (m3(2,2,7)GpppG) with very poor efficiency. Does not hydrolyze unmethylated cap analog (GpppG) and shows no decapping activity on intact m7GpppG-capped mRNA molecules longer than 25 nucleotides. Does not hydrolyze 7-methylguanosine diphosphate (m7GDP) to m7GMP. May also play a role in the 5’->3 mRNA decay pathway; m7GDP, the downstream product released by the 5’->3’ mRNA mediated decapping activity, may be also converted by DCPS to m7GMP. Binds to m7GpppG and strongly to m7GDP. Plays a role in first intron splicing of pre-mRNAs. Inhibits activation-induced cell death.

Subunit / interactions. Homodimer. Associates with components of the exosome multienzyme ribonuclease complex, such as EXOSC3 and EXOSC4. Interacts with NDOR1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Detected in liver, brain, kidney, testis and prostate.

Disease relevance. Al-Raqad syndrome (ARS) [MIM:616459] A syndrome characterized by delayed psychomotor development, moderate to severe intellectual disability, poor or absent speech, microcephaly, congenital hypotonia, and severe growth delay. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The hydrolytic product 7-methylguanosine diphosphate (m7GDP) efficiently inhibits the decapping scavenger activity and acts as a competitive inhibitor in vitro. Inhibited by 2,4-diaminoquinazoline.

Domain organisation. The C-terminal histidine triad (HIT) motif and the N-terminal domain are required for the decapping activity. The N-terminus is necessary but not sufficient for binding cap structures.

Induction. Up-regulated by menadione. Up-regulated by the transcription factor LTF isoform delta-lactoferrin (at protein level).

Similarity. Belongs to the HIT family.

RefSeq proteins (2): NP_001337165, NP_054745* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008594	DcpS/DCS2	Family
IPR011145	Scavenger_mRNA_decap_enz_N	Homologous_superfamily
IPR019808	Histidine_triad_CS	Conserved_site
IPR036265	HIT-like_sf	Homologous_superfamily

Pfam: PF05652, PF11969

Enzyme classification (BRENDA):

• EC 3.6.1.59 — 5’-(N7-methyl 5’-triphosphoguanosine)-[mRNA] diphosphatase (BRENDA: 7 organisms, 80 substrates, 15 inhibitors, 3 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
7-METHYLGUANOSINE 5’-DIPHOSPHATE	0.0003	1
M7G5’PPP5’G	0.0001	1
M32,2,7GPPPG	—	0

Catalyzed reactions (Rhea), 1 shown:

• a 5’-end (N(7)-methyl 5’-triphosphoguanosine)-ribonucleoside in mRNA + H2O = N(7)-methyl-GMP + a 5’-end diphospho-ribonucleoside in mRNA + 2 H(+) (RHEA:65388)

UniProt features (88 total): mutagenesis site 32, strand 17, helix 15, binding site 5, modified residue 5, short sequence motif 3, turn 3, sequence variant 2, initiator methionine 1, chain 1, region of interest 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3BL9	X-RAY DIFFRACTION	1.8
1ST0	X-RAY DIFFRACTION	1.9
1XML	X-RAY DIFFRACTION	2
1ST4	X-RAY DIFFRACTION	2.02
5OSY	X-RAY DIFFRACTION	2.06
3BL7	X-RAY DIFFRACTION	2.31
1XMM	X-RAY DIFFRACTION	2.5
3BLA	X-RAY DIFFRACTION	2.6
4QDV	X-RAY DIFFRACTION	2.8
4QDE	X-RAY DIFFRACTION	2.9
4QEB	X-RAY DIFFRACTION	3.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96C86-F1	89.18	0.79

Functional residue map

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

Catalytic / active sites (1): 277 (nucleophile)

Ligand- & substrate-binding residues (5): 205; 207; 268–279; 175; 185

Post-translational modifications (5): 2, 24, 101, 138, 142

Mutagenesis-validated functional residues (32):

Position	Phenotype
10–13	increases cytoplasmic localization.
58	increases decapping activity to 125% of wild-type.
61	no effect.
63	no effect.
83	strongly reduces decapping activity.
85	reduces decapping activity.
108	reduces decapping activity.
110	loss of decapping activity.
113	loss of decapping activity.
128	no effect.
138	increases decapping activity to 250% of wild-type.
145	increases decapping activity to 180% of wild-type.
146	increases decapping activity to 140% of wild-type.
148	inhibits nuclear export to the cytoplasm.
150	inhibits nuclear export to the cytoplasm.
175	loss of decapping activity.
185	loss of decapping activity.
204	reduces decapping activity.
205	reduces decapping activity.
206	no effect.
207	reduces decapping activity.
207	no effect.
217	no effect.
217	reduces decapping activity.
268	loss of decapping activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease

MSigDB gene sets: 201 (showing top): GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, CAIRO_HEPATOBLASTOMA_DN, GOBP_RNA_SPLICING, AIYAR_COBRA1_TARGETS_DN, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, GOBP_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_DEADENYLATION_DEPENDENT_DECAY

GO Biological Process (6): nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), deadenylation-dependent decapping of nuclear-transcribed mRNA (GO:0000290), mRNA cis splicing, via spliceosome (GO:0045292), mRNA methylguanosine-cap decapping (GO:0110156), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (6): RNA 7-methylguanosine cap binding (GO:0000340), RNA exonuclease activity (GO:0004532), identical protein binding (GO:0042802), 5’-(N(7)-methyl 5’-triphosphoguanosine)-[mRNA] diphosphatase activity (GO:0140932), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nuclear-transcribed mRNA catabolic process	2
mRNA metabolic process	2
RNA processing	2
intracellular membrane-bounded organelle	2
cytoplasm	2
mRNA destabilization	1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
mRNA methylguanosine-cap decapping	1
mRNA splicing, via spliceosome	1
RNA decapping	1
RNA cap binding	1
exonuclease activity	1
RNA nuclease activity	1
protein binding	1
pyrophosphatase activity	1
binding	1
catalytic activity	1
cytoplasmic ribonucleoprotein granule	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCPS	NDOR1	Q9UHB4	952
DCPS	DCP2	Q8IU60	879
DCPS	XRN1	Q8IZH2	851
DCPS	EIF4E	P06730	701
DCPS	NT5C3B	Q969T7	571
DCPS	XRN2	Q9H0D6	563
DCPS	SMN1	Q16637	541
DCPS	EDC4	Q6P2E9	520
DCPS	EDC3	Q96F86	514
DCPS	LSM12	Q3MHD2	503
DCPS	DDX6	P26196	498
DCPS	NUDT16	Q96DE0	495
DCPS	DCP1B	Q8IZD4	490
DCPS	FHIT	P49789	485
DCPS	PARN	O95453	474

IntAct

23 interactions, top by confidence:

A	B	Type	Score
KPNA5	DCPS	psi-mi:“MI:0915”(physical association)	0.560
KPNA6	DCPS	psi-mi:“MI:0915”(physical association)	0.560
KPNA2	DCPS	psi-mi:“MI:0915”(physical association)	0.560
DCPS	DCPS	psi-mi:“MI:0915”(physical association)	0.560
DCPS	SSRP1	psi-mi:“MI:0915”(physical association)	0.400
DCPS	GPC5	psi-mi:“MI:0915”(physical association)	0.370
DCPS	CHST4	psi-mi:“MI:0915”(physical association)	0.370
CDC27	DCPS	psi-mi:“MI:0915”(physical association)	0.370
CSNK2A2	DCPS	psi-mi:“MI:0915”(physical association)	0.370
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
DCPS	KPNA5	psi-mi:“MI:0915”(physical association)	0.000
DCPS	KPNA6	psi-mi:“MI:0915”(physical association)	0.000
DCPS	KPNA2	psi-mi:“MI:0915”(physical association)	0.000
DCPS	DCPS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (405): DCPS (Affinity Capture-RNA), DCPS (Biochemical Activity), CA14 (Affinity Capture-MS), DCPS (Co-fractionation), DCPS (Co-fractionation), DCPS (Co-fractionation), DCPS (Co-fractionation), FLNB (Co-fractionation), DCPS (Affinity Capture-MS), DCPS (Biochemical Activity), DCPS (Biochemical Activity), DCPS (Biochemical Activity), DCPS (Biochemical Activity), IGF2BP3 (Affinity Capture-MS), LRCH3 (Affinity Capture-MS)

ESM2 similar proteins: A1Z8J0, A3LPA1, A5DLC6, A6QXC6, A6ZT79, A7EI75, A7KAI6, A7KAL8, B4N549, D3K0N9, F7W4M2, G2XR75, G5EFS4, I1S0J7, O01757, O16216, O74859, P10363, P22108, P38862, P42744, P87078, Q01879, Q06151, Q09454, Q12123, Q13564, Q4R3L6, Q52CS0, Q5AWA2, Q5ZIE6, Q6CN95, Q6CXW3, Q6FQY7, Q750F5, Q84WU9, Q871U2, Q8K4F7, Q8MIZ3, Q8MJJ7

Diamond homologs: D3K0N9, G5EFS4, Q06151, Q12123, Q8K4F7, Q8MIZ3, Q8MJJ7, Q96C86, Q9DAR7, Q9P7C9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	74
Likely benign	16
Benign	5

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
372233	NM_014026.6(DCPS):c.201+2T>C	Pathogenic
372234	NM_014026.6(DCPS):c.636+1G>A	Pathogenic
1331450	NM_014026.6(DCPS):c.454C>T (p.Arg152Ter)	Likely pathogenic
2445957	NM_014026.6(DCPS):c.856G>T (p.Glu286Ter)	Likely pathogenic
3075731	NM_014026.6(DCPS):c.201+1G>T	Likely pathogenic
430387	NM_014026.6(DCPS):c.562C>T (p.Arg188Trp)	Likely pathogenic

SpliceAI

1663 predictions. Top by Δscore:

Variant	Effect	Δscore
11:126306565:CACA:C	acceptor_loss	1.0000
11:126306567:CAGGT:C	acceptor_loss	1.0000
11:126306568:A:G	acceptor_loss	1.0000
11:126306569:G:A	acceptor_loss	1.0000
11:126331505:G:GT	donor_gain	1.0000
11:126338284:A:AG	acceptor_gain	1.0000
11:126338284:A:AT	acceptor_loss	1.0000
11:126338284:AGT:A	acceptor_gain	1.0000
11:126338284:AGTG:A	acceptor_gain	1.0000
11:126338284:AGTGG:A	acceptor_gain	1.0000
11:126338285:G:GT	acceptor_gain	1.0000
11:126338285:GT:G	acceptor_gain	1.0000
11:126338285:GTG:G	acceptor_gain	1.0000
11:126338285:GTGG:G	acceptor_gain	1.0000
11:126338285:GTGGG:G	acceptor_gain	1.0000
11:126343302:C:CA	acceptor_gain	1.0000
11:126343302:C:G	acceptor_gain	1.0000
11:126343304:CAGCT:C	acceptor_loss	1.0000
11:126343305:A:AG	acceptor_gain	1.0000
11:126343305:AGCTC:A	acceptor_gain	1.0000
11:126343306:G:GA	acceptor_gain	1.0000
11:126343306:GC:G	acceptor_gain	1.0000
11:126343306:GCT:G	acceptor_gain	1.0000
11:126343306:GCTC:G	acceptor_gain	1.0000
11:126343306:GCTCG:G	acceptor_gain	1.0000
11:126343413:GGCAG:G	donor_gain	1.0000
11:126343414:GCAG:G	donor_gain	1.0000
11:126343414:GCAGG:G	donor_gain	1.0000
11:126343416:AGG:A	donor_loss	1.0000
11:126343418:G:GG	donor_gain	1.0000

AlphaMissense

2199 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:126338286:T:A	W175R	0.999
11:126338286:T:C	W175R	0.999
11:126338288:G:C	W175C	0.999
11:126338288:G:T	W175C	0.999
11:126338361:T:C	F200L	0.999
11:126338363:T:A	F200L	0.999
11:126338363:T:G	F200L	0.999
11:126338385:T:A	W208R	0.998
11:126338385:T:C	W208R	0.998
11:126343329:C:A	A220D	0.998
11:126345434:C:G	H279D	0.998
11:126338365:T:A	V201D	0.997
11:126343361:C:A	R231S	0.997
11:126345401:C:G	H268D	0.997
11:126345436:C:A	H279Q	0.997
11:126345436:C:G	H279Q	0.997
11:126338362:T:C	F200S	0.996
11:126338368:T:A	L202H	0.996
11:126338368:T:C	L202P	0.996
11:126338387:G:C	W208C	0.996
11:126338387:G:T	W208C	0.996
11:126343368:T:A	L233H	0.996
11:126343392:T:A	L241H	0.996
11:126343412:G:T	G248W	0.996
11:126345403:C:A	H268Q	0.996
11:126345403:C:G	H268Q	0.996
11:126345428:C:G	H277D	0.996
11:126345432:T:A	V278E	0.996
11:126331432:C:A	A135D	0.995
11:126343332:T:A	I221N	0.995

dbSNP variants (sampled 300 via entrez): RS1000014616 (11:126347525 C>G,T), RS1000028766 (11:126306189 A>G), RS1000112776 (11:126335371 G>A,T), RS1000174057 (11:126318792 C>T), RS1000418740 (11:126326013 G>A), RS1000432914 (11:126324939 T>A,G), RS1000434160 (11:126343504 C>A), RS1000537321 (11:126330500 A>C), RS1000568598 (11:126307683 A>G), RS1000718108 (11:126336971 C>T), RS1000758648 (11:126314482 C>T), RS1000777982 (11:126342803 G>C), RS1000803932 (11:126325157 A>G), RS1000809325 (11:126342536 T>G), RS1000866930 (11:126302106 G>A)

Disease associations

OMIM: gene MIM:610534 | disease phenotypes: MIM:616459

GenCC curated gene-disease

Disease	Classification	Inheritance
Al-Raqad syndrome	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (2): Al-Raqad syndrome (MONDO:0014648), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000369	Low-set ears
HP:0000490	Deeply set eye
HP:0000750	Delayed speech and language development
HP:0001010	Hypopigmentation of the skin
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001631	Atrial septal defect
HP:0001852	Sandal gap
HP:0002066	Gait ataxia
HP:0002540	Inability to walk
HP:0003196	Short nose
HP:0003577	Congenital onset
HP:0012368	Flat face
HP:0012450	Chronic constipation
HP:0025336	Delayed ability to sit
HP:0031936	Delayed ability to walk

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004633_20	Neutrophil percentage of white cells	5.000000e-10
GCST90002381_525	Eosinophil count	3.000000e-18
GCST90002382_399	Eosinophil percentage of white cells	5.000000e-20
GCST90002389_374	Lymphocyte percentage of white cells	3.000000e-09
GCST90002399_323	Neutrophil percentage of white cells	2.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007993	lymphocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1949488 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

9 measured of 9 human assays (9 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-((1-(2-fluorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine	EC50	4 nM
D157555	IC50	9.38 nM
D158963	IC50	23.4 nM
D157493	IC50	43.9 nM
D158885	IC50	101 nM
D156095	EC50	104 nM
D153215	EC50	243 nM
D156676	IC50	339 nM
D157554	EC50	921 nM

ChEMBL bioactivities

46 potent at pChembl≥5 of 51 total, top 46 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL251906
10.70	IC50	0.02	nM	CHEMBL251428
10.52	IC50	0.03	nM	CHEMBL251429
10.52	IC50	0.03	nM	CHEMBL4080254
10.40	IC50	0.04	nM	CHEMBL4082618
10.30	IC50	0.05	nM	CHEMBL255019
10.16	IC50	0.069	nM	CHEMBL4072132
10.10	IC50	0.08	nM	CHEMBL1232147
9.96	IC50	0.11	nM	CHEMBL250072
9.96	IC50	0.11	nM	CHEMBL4077061
9.72	IC50	0.19	nM	CHEMBL398675
9.60	IC50	0.25	nM	CHEMBL4062544
9.57	IC50	0.27	nM	CHEMBL4061457
9.54	IC50	0.29	nM	CHEMBL399673
9.49	IC50	0.32	nM	CHEMBL4076514
9.00	IC50	1.01	nM	CHEMBL342595
8.86	IC50	1.39	nM	CHEMBL4103454
8.75	IC50	1.77	nM	CHEMBL4068466
8.64	IC50	2.3	nM	CHEMBL4072481
8.54	IC50	2.89	nM	CHEMBL250231
8.49	IC50	3.2	nM	CHEMBL342595
8.38	IC50	4.2	nM	CHEMBL4072132
8.12	IC50	7.62	nM	CHEMBL251429
8.10	IC50	7.9	nM	CHEMBL343543
8.03	IC50	9.38	nM	CHEMBL4086727
7.98	IC50	10.55	nM	CHEMBL4075292
7.91	IC50	12.31	nM	CHEMBL4100442
7.87	IC50	13.59	nM	CHEMBL4084161
7.79	IC50	16.2	nM	CHEMBL4090641
7.63	IC50	23.35	nM	CHEMBL4078872
7.52	IC50	30	nM	CHEMBL3351000
7.44	IC50	36	nM	CHEMBL4085817
7.36	IC50	43.94	nM	CHEMBL1232147
6.99	IC50	101.3	nM	CHEMBL4096904
6.85	IC50	142.6	nM	CHEMBL268354
6.48	IC50	334.3	nM	CHEMBL4093512
6.47	IC50	339.4	nM	CHEMBL4090759
6.39	Ki	410	nM	CHEMBL4640425
6.17	Ki	680	nM	CHEMBL1094974
6.14	Ki	730	nM	CHEMBL4635767
6.13	Ki	740	nM	CHEMBL4635767
6.06	Ki	870	nM	CHEMBL4640985
5.75	IC50	1800	nM	CHEMBL1094974
5.51	Ki	3110	nM	CHEMBL4640985
5.03	Ki	9300	nM	CHEMBL4636472
5.01	Ki	9680	nM	CHEMBL4632744

PubChem BioAssay actives

49 with measured affinity, of 98 total; 41 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
5-[(2,4-difluorophenoxy)methyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	<0.0001	uM
4-[(2,4-diaminoquinazolin-5-yl)oxymethyl]benzenesulfonyl fluoride	1553474: Inhibition of DcpS (unknown origin) using m7GpppA as substrate by ELISA	ic50	<0.0001	uM
5-[[1-[(2-fluorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	<0.0001	uM
5-[(2-fluorophenoxy)methyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	<0.0001	uM
5-[[1-[(2-chloro-6-fluorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	<0.0001	uM
5-[(1-benzylpiperidin-4-yl)methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	<0.0001	uM
5-[(3-chlorophenoxy)methyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0001	uM
3-[(2,4-diaminoquinazolin-5-yl)methoxy]-5-fluorobenzonitrile	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0001	uM
5-[[1-[(2,3-dichlorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0001	uM
5-[[1-[(2-chlorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0001	uM
5-[[1-[(2,6-dichlorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0001	uM
5-[(3,5-difluorophenyl)methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0002	uM
5-[(2-chlorophenoxy)methyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0003	uM
5-[(2-methyl-3-pyridinyl)oxymethyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0003	uM
5-[(3-fluorophenoxy)methyl]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0003	uM
5-[[1-[(3,4-dichlorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0003	uM
5-phenylmethoxyquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0010	uM
5-[[1-[[2-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0014	uM
5-(oxan-4-ylmethoxy)quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0018	uM
5-(oxan-4-yloxymethyl)quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0023	uM
5-[(3-chlorophenyl)methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0029	uM
5-methoxyquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0079	uM
5-[[1-[(1-methylimidazol-2-yl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ic50	0.0094	uM
5-[(3-methyloxetan-3-yl)methoxy]quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0106	uM
5-[[1-[(2-fluorophenyl)methyl]piperidin-4-yl]methoxy]-7-methylquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0123	uM
5-[(2S)-1-methoxypropan-2-yl]oxyquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0136	uM
5-[(2R)-1-methoxypropan-2-yl]oxyquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.0162	uM
5-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ic50	0.0233	uM
[4-[(2,4-diaminoquinazolin-5-yl)oxymethyl]piperidin-1-yl]-(3-(125I)iodophenyl)methanone	1949600: Inhibition of human DcpS	ic50	0.0360	uM
5-[[1-(2-chlorophenyl)piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ic50	0.1013	uM
quinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.1426	uM
5-[(2-iodophenoxy)methyl]quinazoline-2,4-diamine	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ec50	0.2430	uM
5-[[1-[(2,6-dichlorophenyl)methyl]piperidin-4-yl]methoxy]-7-methylquinazoline-2,4-diamine	1442738: Inhibition of human DcpS assessed as increase in SMN2 promoter activity	ic50	0.3343	uM
N-[4-[[4-[(2,4-diaminoquinazolin-5-yl)oxymethyl]piperidin-1-yl]methyl]-1,3-thiazol-2-yl]acetamide	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ic50	0.3394	uM
2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[[hydroxy-[hydroxy-[2-(1H-indol-3-yl)ethylamino]phosphoryl]oxyphosphoryl]oxymethyl]oxolan-2-yl]-7-methylpurin-9-ium-6-olate;azane	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	0.4100	uM
[(2R,3S,4R,5R)-5-(2-amino-7-methyl-6-oxo-1H-purin-9-ium-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono phosphate	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	0.6800	uM
2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[[hydroxy-[hydroxy-[2-(1H-indol-3-yl)ethylamino]phosphoryl]oxyphosphinothioyl]oxymethyl]oxolan-2-yl]-7-methylpurin-9-ium-6-olate;azane	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	0.7300	uM
2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[[hydroxy(phosphonooxy)phosphinothioyl]oxymethyl]oxolan-2-yl]-7-methylpurin-9-ium-6-olate	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	0.8700	uM
5-[[1-(piperidin-4-ylmethyl)piperidin-4-yl]methoxy]quinazoline-2,4-diamine	1799427: Biochemical Assay from Article 10.1021/cb800120t: “DcpS as a therapeutic target for spinal muscular atrophy.”	ec50	0.9210	uM
2-amino-9-[(2R,3R,4S,5R)-5-(dihydroxyphosphinothioyloxymethyl)-3,4-dihydroxyoxolan-2-yl]-7-methylpurin-9-ium-6-olate	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	9.3000	uM
2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[[hydroxy-[2-(1H-indol-3-yl)ethylamino]phosphinothioyl]oxymethyl]oxolan-2-yl]-7-methylpurin-9-ium-6-olate;azane	1662727: Inhibition of human DcpS using pyrene labeled 7-methylguanosine triphosphate as substrate preincubated for 15 mins followed by enzyme addition by fluorescence assay	ki	9.6800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Doxorubicin	affects response to substance, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	affects cotreatment, increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
pinostrobin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 20 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1953940	Binding	Binding affinity to human recombinant DcpS by fluorescence quenching titration method	Synthesis and properties of mRNA cap analogs containing imidodiphosphate moiety–fairly mimicking natural cap structure, yet resistant to enzymatic hydrolysis. — Bioorg Med Chem
CHEMBL3608039	ADMET	Stability of the compound assessed as human DcpS-mediated compound hydrolysis at 40 uM after 10 to 180 mins by HPLC analysis	Phosphate-modified analogues of m(7)GTP and m(7)Gppppm(7)G-Synthesis and biochemical properties. — Bioorg Med Chem

Clinical trials (associated diseases)

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