LNPK

Summary

LNPK (lunapark, ER junction formation factor, HGNC:21610) is a protein-coding gene on chromosome 2q31.1, encoding Endoplasmic reticulum junction formation protein lunapark (Q9C0E8). Endoplasmic reticulum (ER)-shaping membrane protein that plays a role in determining ER morphology.

Enables identical protein binding activity. Involved in endoplasmic reticulum tubular network maintenance and positive regulation of endoplasmic reticulum tubular network organization. Located in endoplasmic reticulum tubular network membrane and nucleoplasm.

Source: NCBI Gene 80856 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 91 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• MANE Select transcript: NM_030650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21610
Approved symbol	LNPK
Name	lunapark, ER junction formation factor
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Aliases	Ul, LNP1, LNP
Ensembl gene	ENSG00000144320
Ensembl biotype	protein_coding
OMIM	610236
Entrez	80856

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000272748, ENST00000392540, ENST00000409660, ENST00000431754, ENST00000445472, ENST00000466445, ENST00000475515, ENST00000479012, ENST00000480788, ENST00000483230, ENST00000489827, ENST00000544803, ENST00000878294, ENST00000878295, ENST00000878296, ENST00000918228, ENST00000948632, ENST00000948633, ENST00000948634

RefSeq mRNA: 5 — MANE Select: NM_030650 NM_001305008, NM_001305009, NM_001305010, NM_001305011, NM_030650

CCDS: CCDS33332, CCDS77488, CCDS77489

Canonical transcript exons

ENST00000272748 — 13 exons

Exon	Start	End
ENSE00000964506	175964372	175964423
ENSE00000964507	175947480	175947692
ENSE00000964508	175939552	175939657
ENSE00001133296	175923882	175930199
ENSE00001843532	176002160	176002267
ENSE00003462527	175992231	175992418
ENSE00003522491	175979810	175979868
ENSE00003539897	175995558	175995646
ENSE00003570492	175964506	175964589
ENSE00003616757	175937344	175937514
ENSE00003646535	175938313	175938383
ENSE00003691506	175993182	175993223
ENSE00003791535	175970764	175970804

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 98.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.9831 / max 292.1746, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31941	35.0965	1818
31940	0.7691	419
31943	0.0861	30
31942	0.0314	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.90	gold quality
tibialis anterior	UBERON:0001385	96.51	gold quality
colonic epithelium	UBERON:0000397	93.94	gold quality
ileal mucosa	UBERON:0000331	93.85	gold quality
tendon	UBERON:0000043	93.59	gold quality
bone marrow cell	CL:0002092	92.92	gold quality
deltoid	UBERON:0001476	91.69	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.37	gold quality
adrenal tissue	UBERON:0018303	90.04	gold quality
skeletal muscle tissue	UBERON:0001134	89.99	gold quality
biceps brachii	UBERON:0001507	89.80	gold quality
quadriceps femoris	UBERON:0001377	89.63	gold quality
islet of Langerhans	UBERON:0000006	89.45	gold quality
ganglionic eminence	UBERON:0004023	89.41	gold quality
bone marrow	UBERON:0002371	89.35	gold quality
vastus lateralis	UBERON:0001379	88.92	gold quality
muscle of leg	UBERON:0001383	88.86	gold quality
upper leg skin	UBERON:0004262	88.56	gold quality
muscle tissue	UBERON:0002385	88.42	gold quality
right testis	UBERON:0004534	88.39	gold quality
gastrocnemius	UBERON:0001388	88.29	gold quality
cortical plate	UBERON:0005343	88.14	gold quality
ventricular zone	UBERON:0003053	88.04	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.01	gold quality
left testis	UBERON:0004533	87.79	gold quality
stromal cell of endometrium	CL:0002255	87.46	gold quality
bone element	UBERON:0001474	87.39	gold quality
secondary oocyte	CL:0000655	87.35	gold quality
upper arm skin	UBERON:0004263	87.21	gold quality
left ventricle myocardium	UBERON:0006566	87.01	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

232 targeting LNPK, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7F-2-3P	99.98	70.98	2588

Literature-anchored findings (GeneRIF, showing 10)

• Propose that Lnp1p and Sey1p act antagonistically to balance endoplasmic reticular polygonal network formation. (PMID:22729086)
• Protein N-myristoylation plays a critical role in the endoplasmic reticulum morphological change induced by overexpression of protein Lunapark. (PMID:24223779)
• used live cell imaging to show that mammalian Lnp1 affects endoplasmic reticulum junction mobility and hence network dynamics (PMID:25548161)
• Despite its interaction with gp78, Lnp does not seem to have a broad function in degradation of misfolded ER proteins. (PMID:27387505)
• LNPK was expressed during brain development. (PMID:30032983)
• The proposed mechanism ensures coordinated actions of ATL and Lnp in generating and maintaining three-way junctions. (PMID:30498943)
• CAND1 regulates lunapark for the proper tubular network of the endoplasmic reticulum. (PMID:31511573)
• Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3(KLHL12) Ubiquitin Ligase Complex. (PMID:32433973)
• Roles of the Endogenous Lunapark Protein during Flavivirus Replication. (PMID:34206552)
• Lunapark-dependent formation of a virus-induced ER exit site contains multi-tubular ER junctions that promote viral ER-to-cytosol escape. (PMID:34879280)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	lnpk	ENSDARG00000006639
danio_rerio		ENSDARG00000063646
danio_rerio	lnpa	ENSDARG00000115902
mus_musculus	Lnpk	ENSMUSG00000009207
rattus_norvegicus	Lnpk	ENSRNOG00000001593
drosophila_melanogaster	Lnpk	FBGN0033309
caenorhabditis_elegans		WBGENE00015492

Protein

Protein identifiers

Endoplasmic reticulum junction formation protein lunapark — Q9C0E8 (reviewed: Q9C0E8)

Alternative names: ER junction formation factor lunapark

All UniProt accessions (4): Q9C0E8, C9JL94, C9JM95, H7BZA1

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER)-shaping membrane protein that plays a role in determining ER morphology. Involved in the stabilization of nascent three-way ER tubular junctions within the ER network. May also play a role as a curvature-stabilizing protein within the three-way ER tubular junction network. May be involved in limb development. Is involved in central nervous system development.

Subunit / interactions. Homodimer; homodimerization requires the C4-type zinc finger motif and decreases during mitosis in a phosphorylation-dependent manner.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in neural precursor cells, where it is detected at the growth-cone-like structure and branching sites of neurite-like processes.

Post-translational modifications. Myristoylated; myristoylation is necessary for the endoplasmic reticulum (ER) three-way ER tubular junction formation, but is not required neither for membrane translocation, membrane topology formation, nor for the specific localization to ER membranes. Phosphorylated. Phosphorylation occurs at Ser-177, Ser-182, Ser-217, Ser-227, Ser-321 and Ser-384 during interphase. Phosphorylation occurs at Ser-114, Ser-153, Ser-194, Thr-211 and Ser-353 during mitosis; these phosphorylations reduce both its homodimerization and the ER three-way tubular junction formation. Subject to proteasomal degradation following phosphorylation during mitosis.

Disease relevance. Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum (NEDEHCC) [MIM:618090] An autosomal recessive disorder characterized by severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia. Some patients show mild cerebellar hypoplasia and atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transmembrane domain 1 and 2 function as a signal-anchor and stop-transfer sequence, respectively, generating a double-spanning integral membrane protein with a N- and C-terminal cytoplasmic orientation. Transmembrane domain 1 and 2 are probably sufficient to mediate membrane translocation and topology formation in a N-myristoylation-independent manner. Transmembrane domain 2 is sufficient to block the protein secretion pathway. The two coiled-coil domains are necessary for its endoplasmic reticulum (ER) three-way tubular junction localization. The C4-type zinc finger motif is necessary both for its ER three-way tubular junction localization and formation.

Similarity. Belongs to the lunapark family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9C0E8-1	1	yes
Q9C0E8-2	2
Q9C0E8-3	3
Q9C0E8-4	4

RefSeq proteins (5): NP_001291937, NP_001291938, NP_001291939, NP_001291940, NP_085153* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019273	Lunapark_Znf	Domain
IPR040115	Lnp	Family

Pfam: PF10058

UniProt features (56 total): mutagenesis site 22, modified residue 13, topological domain 3, splice variant 3, coiled-coil region 2, compositionally biased region 2, transmembrane region 2, sequence conflict 2, region of interest 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0E8-F1	68.98	0.32

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 (14): 114, 153, 177, 182, 194, 211, 213, 217, 227, 321, 353, 384, 414, 2

Mutagenesis-validated functional residues (22):

Position	Phenotype
2	abolishes myristoylation. inhibits three-way er tubular junction formation. does not inhibit transmembrane domain 1-indu
177	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
177	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
179	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
179	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
182	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
182	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
194	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
194	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
202	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
202	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
211	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
211	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
213	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
213	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
218	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
218	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
227	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
227	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
231	inhibits phosphorylation and degradation in mitosis and prevents homodimerization and three-way er tubular junction form
231	inhibits phosphorylation and degradation in mitosis but does not prevent homodimerization and three-way er tubular junct
276–301	no change in n-myristoylation. inhibits three-way er tubular junction formation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 222 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, RNGTGGGC_UNKNOWN, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, MODULE_255, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, MODULE_317, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_FORELIMB_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GGGTGGRR_PAX4_03

GO Biological Process (9): endoplasmic reticulum organization (GO:0007029), blood coagulation (GO:0007596), regulation of chondrocyte differentiation (GO:0032330), embryonic forelimb morphogenesis (GO:0035115), embryonic digit morphogenesis (GO:0042733), limb development (GO:0060173), endoplasmic reticulum tubular network organization (GO:0071786), endoplasmic reticulum tubular network maintenance (GO:0071788), positive regulation of endoplasmic reticulum tubular network organization (GO:1903373)

GO Molecular Function (4): zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum tubular network (GO:0071782), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), endoplasmic reticulum tubular network membrane (GO:0098826), sperm head-tail coupling apparatus (GO:0120212)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
sperm flagellum	3
embryonic limb morphogenesis	2
endoplasmic reticulum tubular network organization	2
endoplasmic reticulum subcompartment	2
organelle organization	1
endomembrane system organization	1
hemostasis	1
wound healing	1
coagulation	1
chondrocyte differentiation	1
regulation of cell differentiation	1
regulation of cartilage development	1
forelimb morphogenesis	1
embryonic morphogenesis	1
appendage development	1
endoplasmic reticulum organization	1
cellular component maintenance	1
positive regulation of organelle organization	1
regulation of endoplasmic reticulum tubular network organization	1
transition metal ion binding	1
protein binding	1
binding	1
cation binding	1
nuclear lumen	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum membrane	1
endoplasmic reticulum tubular network	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LNPK	MTX2	O75431	942
LNPK	EVX2	Q03828	880
LNPK	HOXD1	Q9GZZ0	830
LNPK	OR4B1	Q8NGF8	661
LNPK	OR4X2	Q8NGF9	584
LNPK	ATL2	Q8NHH9	571
LNPK	ATL3	Q6DD88	544
LNPK	ATP5MC3	P48201	532
LNPK	TMEM179B	Q7Z7N9	526
LNPK	ATL1	Q8WXF7	475
LNPK	REEP5	Q00765	474
LNPK	RETREG3	Q86VR2	450
LNPK	PDZD8	Q8NEN9	442
LNPK	RTN3	O95197	435
LNPK	TM7SF3	Q9NS93	420

IntAct

92 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
COG7	ILVBL	psi-mi:“MI:0914”(association)	0.640
RANBP6	MUL1	psi-mi:“MI:0914”(association)	0.640
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
CHRNA9	CHEK1	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
ATP1B3	HMGCR	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
SYNPR	LNPK	psi-mi:“MI:0915”(physical association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
LNPK	FOXG1	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
ATG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
COPA	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (407): KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Affinity Capture-MS), KIAA1715 (Proximity Label-MS), KIAA1715 (Proximity Label-MS), KIAA1715 (Proximity Label-MS), KIAA1715 (Proximity Label-MS), KIAA1715 (Proximity Label-MS)

ESM2 similar proteins: A0A1N7SYS3, A1A619, A3LP48, A9ULX8, B0BN56, D4A2Y9, F1NVK6, F6UF99, O04326, P40508, P82908, P82925, P92204, Q02854, Q04935, Q0P5B1, Q1LVV0, Q28GQ3, Q28HF6, Q28X44, Q2UDY8, Q3SYY7, Q3V0J1, Q56VL3, Q5I030, Q5R891, Q5XI29, Q61733, Q659C4, Q66IE4, Q68EU0, Q6AZH0, Q6BI17, Q6CHT7, Q6CJX5, Q6DFB7, Q6DFJ8, Q6NYD7, Q6PFM4, Q75D23

Diamond homologs: A8XK26, Q17667, Q1KKR9, Q1KKT4, Q28HF6, Q5R891, Q6DFJ8, Q6PFM4, Q7TQ95, Q7ZU80, Q9C0E8, Q9ZQ34

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KLHL12	“up-regulates activity”	LNPK	binding
“Cullin 3-RBX1-Skp1”	“up-regulates activity”	LNPK	polyubiquitination
LNPK	“up-regulates activity”	mTORC1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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 SCF-KIT	5	16.1×	7e-04
SLC-mediated transmembrane transport	7	5.4×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	8	25.7×	7e-07
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	6	20.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	40
Likely benign	17
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1028894	NM_030650.3(LNPK):c.1054+1G>C	Pathogenic
4293138	NM_030650.3(LNPK):c.889C>T (p.Arg297Ter)	Pathogenic
559606	NM_030650.3(LNPK):c.726del (p.Pro243fs)	Pathogenic
559607	NM_030650.3(LNPK):c.751C>T (p.Arg251Ter)	Pathogenic
1339220	NM_030650.3(LNPK):c.361G>T (p.Glu121Ter)	Likely pathogenic
2412773	NM_030650.3(LNPK):c.402_405del (p.Leu134fs)	Likely pathogenic
2431477	NM_030650.3(LNPK):c.901dup (p.Cys301fs)	Likely pathogenic

SpliceAI

3774 predictions. Top by Δscore:

Variant	Effect	Δscore
2:175929967:C:CT	donor_gain	1.0000
2:175929967:CTA:C	donor_gain	1.0000
2:175929967:CTACT:C	donor_gain	1.0000
2:175929968:T:TT	donor_gain	1.0000
2:175929995:A:AC	donor_gain	1.0000
2:175929995:AGTT:A	donor_gain	1.0000
2:175929996:G:C	donor_gain	1.0000
2:175930058:T:TA	donor_gain	1.0000
2:175930196:GATT:G	acceptor_gain	1.0000
2:175930197:ATT:A	acceptor_gain	1.0000
2:175930198:TT:T	acceptor_gain	1.0000
2:175930200:C:CC	acceptor_gain	1.0000
2:175937476:T:C	acceptor_gain	1.0000
2:175937487:A:T	acceptor_gain	1.0000
2:175938390:C:CT	acceptor_gain	1.0000
2:175939550:A:C	donor_loss	1.0000
2:175939551:C:G	donor_loss	1.0000
2:175947691:CT:C	acceptor_gain	1.0000
2:175947692:TC:T	acceptor_loss	1.0000
2:175947694:T:A	acceptor_loss	1.0000
2:175964419:CACTC:C	acceptor_gain	1.0000
2:175964421:CTC:C	acceptor_gain	1.0000
2:175964500:TCTTA:T	donor_loss	1.0000
2:175964501:CTTAC:C	donor_loss	1.0000
2:175964503:TAC:T	donor_loss	1.0000
2:175964504:A:AC	donor_gain	1.0000
2:175964504:A:AG	donor_loss	1.0000
2:175964505:C:CC	donor_gain	1.0000
2:175964505:C:CT	donor_loss	1.0000
2:175964586:CAAG:C	acceptor_gain	1.0000

AlphaMissense

2761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:175937495:A:C	C301W	1.000
2:175937496:C:T	C301Y	1.000
2:175937497:A:G	C301R	1.000
2:175937504:A:C	C298W	1.000
2:175937505:C:G	C298S	1.000
2:175937505:C:T	C298Y	1.000
2:175937506:A:G	C298R	1.000
2:175937506:A:T	C298S	1.000
2:175937510:A:C	F296L	1.000
2:175937510:A:T	F296L	1.000
2:175937512:A:G	F296L	1.000
2:175938345:C:T	G284D	1.000
2:175938347:A:C	N283K	1.000
2:175938347:A:T	N283K	1.000
2:175938360:C:G	C279S	1.000
2:175938361:A:G	C279R	1.000
2:175938361:A:T	C279S	1.000
2:175938368:A:C	C276W	1.000
2:175938369:C:G	C276S	1.000
2:175938369:C:T	C276Y	1.000
2:175938370:A:G	C276R	1.000
2:175938370:A:T	C276S	1.000
2:175938375:A:G	L274P	1.000
2:175964530:A:C	F139L	1.000
2:175964530:A:T	F139L	1.000
2:175964532:A:G	F139L	1.000
2:175964540:A:G	L136P	1.000
2:175964552:G:T	A132D	1.000
2:175993198:A:G	L18P	1.000
2:175937483:G:C	N305K	0.999

dbSNP variants (sampled 300 via entrez): RS1000004733 (2:175937377 T>C), RS1000010144 (2:175943494 A>C,G,T), RS1000020963 (2:175976855 G>A), RS1000035682 (2:175931838 G>A), RS1000107149 (2:175951021 G>C), RS1000109927 (2:175950752 T>C), RS1000133400 (2:175940625 T>A,C), RS1000221082 (2:175936265 A>G), RS1000235896 (2:175986158 T>A,C), RS1000284056 (2:175988375 G>A), RS1000284372 (2:176001126 T>C), RS1000284809 (2:175934243 C>T), RS1000377864 (2:175972278 G>A), RS1000429737 (2:175928525 A>C), RS1000467989 (2:175991990 A>G)

Disease associations

OMIM: gene MIM:610236 | disease phenotypes: MIM:618090

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum (MONDO:0060761)

Orphanet (0):

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002123	Generalized myoclonic seizure
HP:0002194	Delayed gross motor development
HP:0002307	Drooling
HP:0002376	Developmental regression
HP:0002540	Inability to walk
HP:0010862	Delayed fine motor development
HP:0011463	Childhood onset
HP:0012434	Delayed early-childhood social milestone development
HP:0031358	Vegetative state
HP:0032792	Tonic seizure

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001588_10	Periodontal microbiota	4.000000e-06
GCST001762_477	Obesity-related traits	8.000000e-06
GCST001762_780	Obesity-related traits	8.000000e-06
GCST001762_900	Obesity-related traits	6.000000e-07
GCST003262_566	Post bronchodilator FEV1	5.000000e-06
GCST006658_18	Longevity	5.000000e-06
GCST007581_5	Carpal tunnel syndrome	7.000000e-11
GCST009464_40	Facial morphology	3.000000e-08
GCST010002_434	Refractive error	5.000000e-25

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake
EFO:0003940	physical activity
EFO:0004314	forced expiratory volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067336 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.54	Kd	286.7	nM	CHEMBL5653589
6.54	ED50	286.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2148658: Binding affinity to human LNP incubated for 45 mins by Kinobead based pull down assay	kd	0.2867	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	decreases expression, affects cotreatment	2
Valproic Acid	decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	decreases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects 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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Flame Retardants	decreases expression	1
Hydrogen Peroxide	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ketoconazole	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651700	Binding	Binding affinity to human LNP 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.