DDRGK1

Summary

DDRGK1 (DDRGK domain containing 1, HGNC:16110) is a protein-coding gene on chromosome 20p13, encoding DDRGK domain-containing protein 1 (Q96HY6). Component of the UFM1 ribosome E3 ligase (UREL) complex, a multiprotein complex that catalyzes ufmylation of endoplasmic reticulum-docked proteins.

The protein encoded by this gene interacts with components of the ubiquitin fold modifier 1 conjugation pathway and helps prevent apoptosis in ER-stressed secretory tissues. In addition, the encoded protein regulates nuclear factor-κB activity.

Source: NCBI Gene 65992 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondyloepimetaphyseal dysplasia, Shohat type (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 185 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• MANE Select transcript: NM_023935

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16110
Approved symbol	DDRGK1
Name	DDRGK domain containing 1
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	dJ1187M17.3, UFBP1
Ensembl gene	ENSG00000198171
Ensembl biotype	protein_coding
OMIM	616177
Entrez	65992

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000354488, ENST00000380201, ENST00000470203, ENST00000496781, ENST00000897091, ENST00000897092, ENST00000897093, ENST00000897094, ENST00000926205, ENST00000926206, ENST00000926207, ENST00000926208, ENST00000941356, ENST00000941357, ENST00000941358, ENST00000941359

RefSeq mRNA: 1 — MANE Select: NM_023935 NM_023935

CCDS: CCDS13050

Canonical transcript exons

ENST00000354488 — 9 exons

Exon	Start	End
ENSE00000656665	3191190	3191238
ENSE00000656668	3195231	3195353
ENSE00000858727	3200342	3200454
ENSE00000858728	3203213	3203416
ENSE00001044113	3200001	3200102
ENSE00003465996	3190350	3190819
ENSE00003580578	3194830	3194868
ENSE00003591371	3191765	3191821
ENSE00003846451	3204537	3204682

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.1560 / max 228.7167, expressed in 1820 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186142	48.1560	1820

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	97.66	gold quality
right adrenal gland	UBERON:0001233	97.22	gold quality
right adrenal gland cortex	UBERON:0035827	97.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.05	gold quality
left adrenal gland	UBERON:0001234	96.93	gold quality
right frontal lobe	UBERON:0002810	96.70	gold quality
left adrenal gland cortex	UBERON:0035825	96.68	gold quality
cerebellar hemisphere	UBERON:0002245	96.63	gold quality
cerebellar cortex	UBERON:0002129	96.56	gold quality
mucosa of stomach	UBERON:0001199	96.52	gold quality
adrenal cortex	UBERON:0001235	96.34	gold quality
body of pancreas	UBERON:0001150	96.32	gold quality
prefrontal cortex	UBERON:0000451	96.26	gold quality
sural nerve	UBERON:0015488	96.16	gold quality
anterior cingulate cortex	UBERON:0009835	96.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.13	gold quality
cingulate cortex	UBERON:0003027	96.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.04	gold quality
adrenal gland	UBERON:0002369	95.90	gold quality
body of stomach	UBERON:0001161	95.71	gold quality
cerebellum	UBERON:0002037	95.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.55	gold quality
cervix squamous epithelium	UBERON:0006922	95.51	silver quality
minor salivary gland	UBERON:0001830	95.43	gold quality
right lung	UBERON:0002167	95.40	gold quality
endocervix	UBERON:0000458	95.39	gold quality
nucleus accumbens	UBERON:0001882	95.39	gold quality
tibial nerve	UBERON:0001323	95.23	gold quality
putamen	UBERON:0001874	95.14	gold quality
saliva-secreting gland	UBERON:0001044	95.13	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.46
E-MTAB-7606	no	684.46
E-MTAB-6142	no	70.67

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CCND1	Activation
CX3CL1	Activation
MMP9	Activation
NFKBIA	Repression
SAA2	Activation

miRNA regulators (miRDB)

13 targeting DDRGK1, 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-4650-5P	99.98	64.69	999
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-5187-5P	98.54	67.94	952
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-6757-5P	98.08	65.50	724
HSA-MIR-4438	97.96	63.70	947
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-4661-3P	96.81	66.02	342

Literature-anchored findings (GeneRIF, showing 10)

• found that C53/LZAP and DDRGK1 became more susceptible to the proteasome-mediated degradation in RCAD knockdown cells, whereas their ubiquitination was significantly attenuated by RCAD overexpression (PMID:20228063)
• DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability. (PMID:23675531)
• Study results provide evidence that DDRGK1 is essential for endoplasmic reticulum (ER) homeostasis regulation in both human cancer cells and mouse hematopoietic stem cells. Depletion of DDRGK1 activates apoptotic pathway by targeting the ER-stress sensor IRE1alpha. DDRGK1 regulates IRE1alpha protein stability via its interaction with the kinase domain of IRE1alpha. (PMID:28128204)
• Loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia. (PMID:28263186)
• we screened the susceptibility loci for Myocardial infarction (MI) using exome sequencing and validated candidate variants in replication sets. We identified that three genes (GYG1, DIS3L and DDRGK1) were associated with MI at the discovery and replication stages. (PMID:29321365)
• UFBP1 expression downregulates the protein level and reduces the stability of several of its interacting proteins; promotes their ubiquitination and degradation (PMID:29533670)
• Prognostic analysis showed that the co-expression of CDK5RAP3 and DDRGK1 was an independent prognostic factor correlating with the overall survival of gastric cancer patients. (PMID:30228783)
• UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2. (PMID:33219317)
• A missense mutation in DDRGK1 gene associated to Shohat-type spondyloepimetaphyseal dysplasia: Two case reports and a review of literature. (PMID:35670300)
• DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination. (PMID:36965071)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ddrgk1	ENSMUSG00000068290
rattus_norvegicus	Ddrgk1	ENSRNOG00000021232
drosophila_melanogaster	Ddrgk1	FBGN0038868
caenorhabditis_elegans		WBGENE00022865

Protein

Protein identifiers

DDRGK domain-containing protein 1 — Q96HY6 (reviewed: Q96HY6)

Alternative names: Dashurin, UFM1-binding and PCI domain-containing protein 1

All UniProt accessions (2): A0A0A0MRX2, Q96HY6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the UFM1 ribosome E3 ligase (UREL) complex, a multiprotein complex that catalyzes ufmylation of endoplasmic reticulum-docked proteins. The UREL complex plays a key role in ribosome recycling by mediating mono-ufmylation of the RPL26/uL24 subunit of the 60S ribosome following ribosome dissociation: ufmylation weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane. Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum. Within the UREL complex, DDRGK1 tethers the complex to the endoplasmic reticulum membrane to restrict its activity to endoplasmic reticulum-docked ribosomes and acts as an ufmylation ‘reader’: following RPL26/uL24 ufmylation, DDRGK1 specifically binds to ufmylated RPL26/uL24 via its UFIM motif, resulting in stable association between the 60S ribosome and the UREL complex, followed by dissociation of the 60S ribosome subunit from the endoplasmic reticulum membrane. The UREL complex is also involved in reticulophagy in response to endoplasmic reticulum stress by promoting ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins. Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability. Acts as a regulator of immunity by promoting differentiation of B-cells into plasma cells: acts by promoting expansion of the endoplasmic reticulum and regulating the unfolded protein response (UPR). May also be required for TRIP4 ufmylation. May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B. Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator. Required for stabilization and ufmylation of ATG9A.

Subunit / interactions. Component of the UFM1 ribosome E3 ligase (UREL) complex, composed of UFL1, DDRGK1 and CDK5RAP3. Interacts with (unphosphorylated) ERN1/IRE1-alpha; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability. Interacts with NFKBIA. Interacts with SOX9.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed (at protein level). In the brain, highest levels in medulla oblongata, followed by cerebral cortex, cerebellum and frontal lobe.

Post-translational modifications. Ubiquitinated. Ubiquitination probably triggers proteasomal degradation and is negatively regulated by UFL1, the enzyme involved in the ufmylation of DDRGK1. Ufmylated; conjugated to ubiquitin-like protein UFM1, probably at Lys-267 by UFL1. The relevance of ufmylation is however unclear: as DDRGK1 acts as a substrate adapters for ufmylation, it is uncertain whether ufmylation is a collateral effect of ufmylation process or is required to regulate its activity.

Disease relevance. Spondyloepimetaphyseal dysplasia, Shohat type (SEMDSH) [MIM:602557] An autosomal recessive skeletal dysplasia that affects cartilage development. It is characterized by vertebral, epiphyseal, and metaphyseal abnormalities, including scoliosis with vertebral compression fractures, flattened vertebral bodies, and hypomineralization of long bones. Affected individuals may exhibit a small trunk, short neck, small limbs, joint laxity, bowlegs, and/or abdominal distension with hepatosplenomegaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The UFM1-interacting motif (UFIM) specifically recognizes and binds ufmylated RPL26/uL24, resulting in stable association between the 60S ribosome and the UREL complex.

Similarity. Belongs to the DDRGK1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96HY6-1	1	yes
Q96HY6-2	2

RefSeq proteins (1): NP_076424* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019153	DDRGK_dom-contain	Family
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050899	DDRGK_domain-containing	Family

Pfam: PF09756

UniProt features (42 total): mutagenesis site 17, helix 5, region of interest 5, strand 4, modified residue 2, chain 1, transmembrane region 1, compositionally biased region 1, cross-link 1, splice variant 1, sequence variant 1, topological domain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7W3N	X-RAY DIFFRACTION	1.6
8C0D	X-RAY DIFFRACTION	2.56
8OJ5	ELECTRON MICROSCOPY	2.9
9GY4	ELECTRON MICROSCOPY	3
8B9X	X-RAY DIFFRACTION	3.07
8OHD	ELECTRON MICROSCOPY	3.1
8QFC	ELECTRON MICROSCOPY	3.2
8OJ0	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HY6-F1	75.52	0.40

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 (3): 72, 114, 267

Mutagenesis-validated functional residues (17):

Position	Phenotype
116–128	impairs some post-translational modification without affecting interaction with ufl1; when associated with r-146, r-176,
116	weak or no effect on ufmylation.
121	weak or no effect on ufmylation.
124	weak or no effect on ufmylation.
128	weak or no effect on ufmylation.
146	impairs some post-translational modification without affecting interaction with ufl1; when associated with 116-r–r-128,
176	impairs some post-translational modification without affecting interaction with ufl1; when associated with 116-r–r-128,
193	weak or no effect on ufmylation. impairs some post-translational modification without affecting interaction with ufl1; w
196–201	abolished ability to recognize and bind ufmylated rpl26/ul24.
196–198	abolished ability to recognize and bind ufmylated rpl26/ul24.
224–227	impairs some post-translational modification without affecting interaction with ufl1; when associated with 116-r–r-128,
224	weak or no effect on ufmylation.
227	weak or no effect on ufmylation.
265	decreased ribosome ufmylation.
267	impairs interaction with ufl1 and ufmylation. impairs interaction with ern1/ire1-alpha and ability to regulate its stabi
271–276	abolished interaction with ufl1; when associated with 302-a–a-304.
302–304	abolished interaction with ufl1; when associated with 271-a–a-276.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8980692	RHOA GTPase cycle

MSigDB gene sets: 361 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (30): positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of cell migration (GO:0030335), regulation of protein stability (GO:0031647), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), ribosome disassembly (GO:0032790), regulation of intracellular estrogen receptor signaling pathway (GO:0033146), response to endoplasmic reticulum stress (GO:0034976), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of transcription by RNA polymerase II (GO:0045944), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), cartilage development (GO:0051216), reticulophagy (GO:0061709), protein localization to endoplasmic reticulum (GO:0070972), protein ufmylation (GO:0071569), rescue of stalled cytosolic ribosome (GO:0072344), positive regulation of reticulophagy (GO:0140501), positive regulation of plasma cell differentiation (GO:1900100), positive regulation of proteasomal protein catabolic process (GO:1901800), positive regulation of cell cycle G1/S phase transition (GO:1902808), obsolete positive regulation of proteolysis involved in protein catabolic process (GO:1903052), positive regulation of I-kappaB phosphorylation (GO:1903721), negative regulation of IRE1-mediated unfolded protein response (GO:1903895), negative regulation of PERK-mediated unfolded protein response (GO:1903898), positive regulation of protein localization to endoplasmic reticulum (GO:1905552), protein K69-linked ufmylation (GO:1990592), blood circulation (GO:0008015)

GO Molecular Function (3): ubiquitin-like protein ligase binding (GO:0044389), UFM1-modified protein reader activity (GO:0141185), protein binding (GO:0005515)

GO Cellular Component (5): nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gene expression	2
regulation of gene expression	2
regulation of proteasomal ubiquitin-dependent protein catabolic process	2
proteasome-mediated ubiquitin-dependent protein catabolic process	2
cellular anatomical structure	2
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
regulation of biological quality	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
organelle disassembly	1
estrogen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
cellular response to stress	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
skeletal system development	1
animal organ development	1
connective tissue development	1
macroautophagy	1
protein localization to organelle	1
protein modification by small protein conjugation	1
cytoplasmic translational elongation	1
ribosome disassembly	1
positive regulation of macroautophagy	1

Protein interactions and networks

STRING

2662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDRGK1	UFL1	O94874	977
DDRGK1	UFM1	P61960	961
DDRGK1	CDK5RAP3	Q96JB5	909
DDRGK1	UFSP2	Q9NUQ7	897
DDRGK1	UBA5	Q9GZZ9	844
DDRGK1	UFC1	Q9Y3C8	843
DDRGK1	UFSP1	Q6NVU6	787
DDRGK1	ERN1	O75460	593
DDRGK1	SIPA1L2	Q9P2F8	567
DDRGK1	TRIP4	Q15650	507
DDRGK1	VPS13C	Q709C8	466
DDRGK1	RPL26	P61254	464
DDRGK1	ZNF366	Q8N895	426
DDRGK1	UBOX5	O94941	420
DDRGK1	ZNF367	Q7RTV3	410

IntAct

80 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
CDK5RAP3	UFL1	psi-mi:“MI:0914”(association)	0.870
UFC1	UFL1	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UFL1	DDRGK1	psi-mi:“MI:0914”(association)	0.710
DDRGK1	UFL1	psi-mi:“MI:0914”(association)	0.710
DDRGK1	UFL1	psi-mi:“MI:0915”(physical association)	0.710
UFL1	DDRGK1	psi-mi:“MI:0915”(physical association)	0.710
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
GRAMD2B	EFCAB14	psi-mi:“MI:0914”(association)	0.530
SRPRB	CTDNEP1	psi-mi:“MI:0914”(association)	0.530
PSG3	MGRN1	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP	psi-mi:“MI:0914”(association)	0.530
DDRGK1	CFTR	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
DDRGK1	HTR6	psi-mi:“MI:0915”(physical association)	0.370
Ufl1	PRSS1	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

BioGRID (1411): DDRGK1 (Affinity Capture-MS), SRPR (Affinity Capture-MS), MYO18A (Affinity Capture-MS), PLS1 (Affinity Capture-MS), TRIM26 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), RMND1 (Affinity Capture-MS), UFC1 (Affinity Capture-MS), DPY19L3 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS)

ESM2 similar proteins: A7SK48, A8QFY9, A8WM57, A9UQM0, B0W6N3, B0WIW5, B3LY22, B3MTS7, B3P045, B3P211, B3S3D5, B4GDX4, B4GMC4, B4I3P3, B4JG35, B4KA44, B4KB40, B4LYB9, B4M693, B4NIC3, B4NKL1, B4PQC4, B4PTS9, B4QVI2, B4R133, B5DFC8, B5ME19, C0KYB6, C1BL82, C3Y431, P34623, Q173M7, Q1LZB0, Q27371, Q295B1, Q295G5, Q3SYW6, Q55CM7, Q5RAT8, Q6NXA9

Diamond homologs: A8QFY9, A9UQM0, B0WIW5, B3MTS7, B3P045, B3S3D5, B4GMC4, B4JG35, B4KB40, B4LYB9, B4NKL1, B4PQC4, B4R133, C0KYB6, C1BL82, C3Y431, P34623, Q1LZB0, Q295B1, Q55CM7, Q6P0E5, Q80WW9, Q8LH03, Q94C53, Q96HY6, Q9VDD1, Q8IIG1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	36.6×	2e-05
Downstream signal transduction	6	32.2×	4e-06
Signaling by FGFR1 in disease	5	20.6×	1e-04
Signaling by SCF-KIT	5	17.5×	2e-04
Constitutive Signaling by Aberrant PI3K in Cancer	6	10.7×	4e-04
Signaling by ALK fusions and activated point mutants	5	10.6×	1e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	7	9.5×	2e-04
PIP3 activates AKT signaling	9	8.5×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	8	16.2×	3e-05
liver development	5	12.9×	4e-03
response to endoplasmic reticulum stress	6	11.6×	2e-03
MAPK cascade	6	10.7×	3e-03
protein autophosphorylation	6	10.1×	3e-03
positive regulation of MAPK cascade	9	8.4×	4e-04
positive regulation of cell migration	11	7.9×	7e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	7.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	85
Likely benign	60
Benign	13

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1458541	NC_000020.10:g.(?3180627)(3199298_?)del	Pathogenic
2073894	NM_023935.3(DDRGK1):c.391C>T (p.Arg131Ter)	Pathogenic
487527	NM_023935.3(DDRGK1):c.408+1G>A	Pathogenic
816102	GRCh37/hg19 20p13-11.1(chr20:61568-26305479)x3	Pathogenic
2875647	NM_023935.3(DDRGK1):c.510+2T>G	Likely pathogenic

SpliceAI

1239 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3190816:ACACC:A	acceptor_loss	1.0000
20:3190817:CAC:C	acceptor_gain	1.0000
20:3190818:ACC:A	acceptor_loss	1.0000
20:3190820:C:CG	acceptor_loss	1.0000
20:3191759:GCTTA:G	donor_loss	1.0000
20:3191760:CTTA:C	donor_loss	1.0000
20:3191761:TTA:T	donor_loss	1.0000
20:3191762:TAC:T	donor_loss	1.0000
20:3191763:ACC:A	donor_loss	1.0000
20:3191764:C:G	donor_loss	1.0000
20:3191819:CTG:C	acceptor_gain	1.0000
20:3191820:TG:T	acceptor_gain	1.0000
20:3191822:C:CC	acceptor_gain	1.0000
20:3191825:C:CT	acceptor_gain	1.0000
20:3191826:A:T	acceptor_gain	1.0000
20:3194869:C:CC	acceptor_gain	1.0000
20:3195226:CCCA:C	donor_loss	1.0000
20:3195227:CCAC:C	donor_loss	1.0000
20:3195228:CAC:C	donor_loss	1.0000
20:3195235:T:A	donor_gain	1.0000
20:3195256:ACG:A	donor_gain	1.0000
20:3195257:CGC:C	donor_gain	1.0000
20:3195262:T:TA	donor_gain	1.0000
20:3195283:T:TA	donor_gain	1.0000
20:3195349:TCCTC:T	acceptor_gain	1.0000
20:3195350:CCTCC:C	acceptor_gain	1.0000
20:3195351:CTC:C	acceptor_gain	1.0000
20:3195352:TC:T	acceptor_gain	1.0000
20:3195353:CC:C	acceptor_gain	1.0000
20:3195354:C:CC	acceptor_gain	1.0000

AlphaMissense

2000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3190804:C:G	R265P	0.997
20:3191225:C:G	R248P	0.997
20:3190786:A:T	I271K	0.996
20:3190795:A:G	F268S	0.996
20:3190819:C:T	G260D	0.996
20:3191213:A:G	L252P	0.995
20:3200346:C:G	R135P	0.994
20:3190717:A:T	L294H	0.993
20:3190771:A:G	L276P	0.993
20:3191790:G:T	A235D	0.993
20:3191793:A:G	L234P	0.993
20:3195276:A:C	F196L	0.993
20:3195276:A:T	F196L	0.993
20:3195278:A:G	F196L	0.993
20:3200390:C:A	K120N	0.993
20:3200390:C:G	K120N	0.993
20:3190717:A:G	L294P	0.992
20:3190801:C:A	G266V	0.992
20:3190810:T:A	D263V	0.992
20:3191190:C:G	G260R	0.992
20:3195289:A:G	L192P	0.992
20:3190704:G:C	S298R	0.991
20:3190704:G:T	S298R	0.991
20:3190706:T:G	S298R	0.991
20:3190801:C:T	G266D	0.991
20:3200086:C:G	R142P	0.991
20:3200102:C:G	A137P	0.991
20:3190786:A:C	I271R	0.990
20:3190811:C:G	D263H	0.990
20:3195298:T:C	Y189C	0.990

dbSNP variants (sampled 300 via entrez): RS1000557664 (20:3203394 A>G), RS1000829818 (20:3190048 T>C,G), RS1000856079 (20:3196817 T>C,G), RS1000869197 (20:3196851 C>T), RS1000921581 (20:3197013 A>C), RS1000978016 (20:3202859 G>C), RS1001239883 (20:3198635 G>A), RS1001255791 (20:3203759 G>A), RS1001412470 (20:3191593 TC>T), RS1001484213 (20:3192228 C>T), RS1001595473 (20:3198321 T>A,C), RS1001657255 (20:3194419 T>C), RS1001831810 (20:3203041 G>A), RS1001879512 (20:3197950 A>G), RS1001947319 (20:3199910 C>T)

Disease associations

OMIM: gene MIM:616177 | disease phenotypes: MIM:602557, MIM:613850, MIM:614749

GenCC curated gene-disease

Disease	Classification	Inheritance
spondyloepimetaphyseal dysplasia, Shohat type	Strong	Autosomal recessive

Mondo (3): spondyloepimetaphyseal dysplasia, Shohat type (MONDO:0011252), inosine triphosphatase deficiency (MONDO:0013461), hyperphosphatasia with intellectual disability syndrome 2 (MONDO:0013882)

Orphanet (3): Spondyloepimetaphyseal dysplasia, Shohat type (Orphanet:93352), Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262), NON RARE IN EUROPE: Inosine triphosphate pyrophosphatase deficiency (Orphanet:319684)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000233	Thin vermilion border
HP:0000470	Short neck
HP:0000773	Short ribs
HP:0000926	Platyspondyly
HP:0001382	Joint hypermobility
HP:0001433	Hepatosplenomegaly
HP:0001591	Bell-shaped thorax
HP:0001602	Laryngeal stenosis
HP:0001609	Hoarse voice
HP:0001744	Splenomegaly
HP:0002240	Hepatomegaly
HP:0002650	Scoliosis
HP:0002651	Spondyloepimetaphyseal dysplasia
HP:0002663	Delayed epiphyseal ossification
HP:0002777	Tracheal stenosis
HP:0002781	Upper airway obstruction
HP:0002812	Coxa vara
HP:0002829	Arthralgia
HP:0002938	Lumbar hyperlordosis
HP:0002953	Vertebral compression fracture
HP:0002970	Genu varum
HP:0002979	Bowing of the legs
HP:0002983	Micromelia
HP:0003015	Flared metaphysis
HP:0003016	Metaphyseal widening
HP:0003025	Metaphyseal irregularity
HP:0003026	Short long bone
HP:0003088	Premature osteoarthritis
HP:0003099	Fibular overgrowth

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000729_1	Ribavirin-induced anemia	4.000000e-44
GCST001094_1	Response to hepatitis C treatment	5.000000e-17
GCST001094_3	Response to hepatitis C treatment	9.000000e-25
GCST002544_8	Parkinson’s disease	3.000000e-11
GCST003542_168	Night sleep phenotypes	9.000000e-06
GCST004902_14	Parkinson’s disease	2.000000e-06
GCST009325_107	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-11
GCST009613_3	HDL cholesterol levels x loop diuretics use interaction	3.000000e-07
GCST010002_59	Refractive error	6.000000e-11
GCST90013407_152	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004272	anemia (phenotype)
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564127	Inosine Triphosphatase Deficiency (supp.)
C566523	Spondyloepimetaphyseal Dysplasia, Shohat Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067221 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1127354	Efficacy	3	azathioprine	Inflammatory Bowel Diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1127354	DDRGK1, ITPA	2B	23.50	7	methotrexate;azathioprine;purine analogues;azathioprine;interferon alfa-2b;recombinant;ribavirin;mercaptopurine;peginterferon alfa-2b;ribavirin
rs2295553	DDRGK1		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	57.84	nM	CHEMBL5653589
7.24	ED50	57.84	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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	2148213: Binding affinity to human DDRGK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0578	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression	2
sodium arsenite	increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
deoxynivalenol	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
tetrabromobisphenol A	decreases expression	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Diethylhexyl Phthalate	increases abundance, decreases methylation	1
Ivermectin	decreases expression	1
Potassium Dichromate	increases expression	1
Smoke	decreases expression	1
Valproic Acid	affects expression	1
Sodium Selenite	increases expression	1
Thapsigargin	increases expression	1
Genistein	decreases expression, increases reaction	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
CHEMBL5651255	Binding	Binding affinity to human DDRGK1 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)

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