UNC50

Summary

UNC50 (unc-50 inner nuclear membrane RNA binding protein, HGNC:16046) is a protein-coding gene on chromosome 2q11.2, encoding Protein unc-50 homolog (Q53HI1). Involved in the cell surface expression of neuronal nicotinic receptors. It is a selective cancer dependency (DepMap: 42.5% of cell lines).

Predicted to enable RNA binding activity. Predicted to be involved in protein localization to cell surface. Predicted to be located in nuclear inner membrane. Predicted to be active in Golgi membrane.

Source: NCBI Gene 25972 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arthrogryposis multiplex congenita (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 49 total
• Cancer dependency (DepMap): dependent in 42.5% of screened cell lines
• MANE Select transcript: NM_014044

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16046
Approved symbol	UNC50
Name	unc-50 inner nuclear membrane RNA binding protein
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	URP, UNCL, GMH1
Ensembl gene	ENSG00000115446
Ensembl biotype	protein_coding
OMIM	617826
Entrez	25972

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 23 protein_coding, 1 retained_intron

ENST00000357765, ENST00000393493, ENST00000409347, ENST00000409975, ENST00000423713, ENST00000466492, ENST00000903454, ENST00000903455, ENST00000903456, ENST00000917837, ENST00000917838, ENST00000917839, ENST00000917840, ENST00000917841, ENST00000917842, ENST00000917843, ENST00000917844, ENST00000917845, ENST00000945504, ENST00000945505, ENST00000945506, ENST00000945507, ENST00000945508, ENST00000945509

RefSeq mRNA: 3 — MANE Select: NM_014044 NM_001330353, NM_001330354, NM_014044

CCDS: CCDS2035, CCDS82485

Canonical transcript exons

ENST00000357765 — 6 exons

Exon	Start	End
ENSE00000771567	98610775	98610895
ENSE00000804222	98616207	98616346
ENSE00000804223	98616432	98616533
ENSE00001408008	98609756	98610039
ENSE00001409832	98608589	98608726
ENSE00001586170	98618168	98618515

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 96.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6320 / max 123.6232, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21551	21.6320	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	96.64	gold quality
adenohypophysis	UBERON:0002196	96.43	gold quality
left lobe of thyroid gland	UBERON:0001120	96.24	gold quality
right lobe of thyroid gland	UBERON:0001119	96.08	gold quality
body of pancreas	UBERON:0001150	96.05	gold quality
right lung	UBERON:0002167	96.05	gold quality
body of uterus	UBERON:0009853	95.93	gold quality
thyroid gland	UBERON:0002046	95.91	gold quality
pituitary gland	UBERON:0000007	95.86	gold quality
germinal epithelium of ovary	UBERON:0001304	95.83	gold quality
calcaneal tendon	UBERON:0003701	95.83	gold quality
pigmented layer of retina	UBERON:0001782	95.78	gold quality
endocervix	UBERON:0000458	95.74	gold quality
tibial nerve	UBERON:0001323	95.68	gold quality
right ovary	UBERON:0002118	95.65	gold quality
right testis	UBERON:0004534	95.53	gold quality
islet of Langerhans	UBERON:0000006	95.52	gold quality
right uterine tube	UBERON:0001302	95.50	gold quality
left ovary	UBERON:0002119	95.50	gold quality
ascending aorta	UBERON:0001496	95.44	gold quality
left testis	UBERON:0004533	95.44	gold quality
right coronary artery	UBERON:0001625	95.43	gold quality
thoracic aorta	UBERON:0001515	95.41	gold quality
parotid gland	UBERON:0001831	95.41	gold quality
metanephros cortex	UBERON:0010533	95.40	gold quality
minor salivary gland	UBERON:0001830	95.39	gold quality
saliva-secreting gland	UBERON:0001044	95.38	gold quality
rectum	UBERON:0001052	95.30	gold quality
left coronary artery	UBERON:0001626	95.23	gold quality
body of stomach	UBERON:0001161	95.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting UNC50, 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-1277-5P	100.00	73.95	5056
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-4662A-3P	97.02	67.77	941
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• UNCL plays important roles in the development, differentiation, and maintenance of periodontal tissues and in the mechanotransduction of periodontal ligament fibroblasts. (PMID:17004066)
• UNC50 may plays some roles in HCC progression by affecting the EGFR pathway (PMID:25738771)
• depletion of UNC50 blocked early endosome-to-Golgi trafficking and induced lysosomal degradation of STx2. UNC50 acted by recruiting GBF1, an ADP ribosylation factor-guanine nucleotide exchange factor (ARF-GEF), to the Golgi. (PMID:28883040)
• Data indicate that biallelic mutation in the UNC50 gene underlies AMC through a probable loss of AChR expression at the neuromuscular junction which is essential for the cholinergic transmission during human muscle development. (PMID:29016857)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc50	ENSDARG00000040455
mus_musculus	Unc50	ENSMUSG00000026111
rattus_norvegicus	Unc50	ENSRNOG00000018128
drosophila_melanogaster	Unc50	FBGN0037609
caenorhabditis_elegans		WBGENE00006785

Protein

Protein identifiers

Protein unc-50 homolog — Q53HI1 (reviewed: Q53HI1)

Alternative names: Periodontal ligament-specific protein 22, Protein GMH1 homolog, Uncoordinated-like protein

All UniProt accessions (5): Q53HI1, A0A0S2Z612, H7BYK3, H7C3J5, J3KQ47

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the cell surface expression of neuronal nicotinic receptors. Binds RNA.

Subcellular location. Nucleus inner membrane. Golgi apparatus membrane.

Tissue specificity. Present in periodontal ligament fibroblasts (at protein level).

Similarity. Belongs to the unc-50 family.

RefSeq proteins (3): NP_001317282, NP_001317283, NP_054763* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007881	UNC-50	Family

Pfam: PF05216

UniProt features (19 total): topological domain 6, transmembrane region 5, sequence conflict 5, modified residue 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53HI1-F1	88.86	0.73

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 (2): 1, 6

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 107 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, AP2_Q3, MCBRYAN_PUBERTAL_BREAST_5_6WK_UP, TIEN_INTESTINE_PROBIOTICS_24HR_UP, GOBP_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, GOCC_NUCLEAR_ENVELOPE, ATGTACA_MIR493, GOCC_ORGANELLE_INNER_MEMBRANE, GOCC_NUCLEAR_INNER_MEMBRANE, GOCC_NUCLEAR_MEMBRANE, SCGGAAGY_ELK1_02, MULLIGHAN_MLL_SIGNATURE_1_UP, chr2q11, MCBRYAN_PUBERTAL_BREAST_6_7WK_DN

GO Biological Process (1): protein localization to cell surface (GO:0034394)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (5): Golgi membrane (GO:0000139), nuclear inner membrane (GO:0005637), nucleus (GO:0005634), Golgi apparatus (GO:0005794), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
intracellular protein localization	1
nucleic acid binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle inner membrane	1
nuclear membrane	1
cytoplasm	1
endomembrane system	1
cellular anatomical structure	1

Protein interactions and networks

STRING

822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC50	RIC3	Q7Z5B4	858
UNC50	TMX3	Q96JJ7	677
UNC50	GOSR1	O95249	664
UNC50	TM9SF2	Q99805	545
UNC50	TMEM165	Q9HC07	502
UNC50	VPS51	Q9UID3	494
UNC50	CDC42EP2	O14613	478
UNC50	PIGZ	Q86VD9	473
UNC50	UXS1	Q8NBZ7	467
UNC50	A0A0A6YYG9	A0A0A6YYG9	456
UNC50	AKAP17A	Q02040	453
UNC50	IZUMO2	Q6UXV1	447
UNC50	PIGO	Q8TEQ8	442
UNC50	B4GALT5	O43286	438
UNC50	ARHGAP6	O43182	434
UNC50	GBF1	Q92538	434

IntAct

106 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
UNC50	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
UNC50	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
UNC50	GPX8	psi-mi:“MI:0915”(physical association)	0.560
UNC50	SGPL1	psi-mi:“MI:0915”(physical association)	0.560
UNC50	EBP	psi-mi:“MI:0915”(physical association)	0.560
UNC50	FFAR2	psi-mi:“MI:0915”(physical association)	0.560
UNC50	DARS2	psi-mi:“MI:0915”(physical association)	0.560
UNC50	AQP6	psi-mi:“MI:0915”(physical association)	0.560
UNC50	MFF	psi-mi:“MI:0915”(physical association)	0.560
UNC50	TMED8	psi-mi:“MI:0915”(physical association)	0.560
UNC50	CLEC10A	psi-mi:“MI:0915”(physical association)	0.560
UNC50	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
UNC50	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
UNC50	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
MGST3	UNC50	psi-mi:“MI:0915”(physical association)	0.560
UNC50	MFSD14B	psi-mi:“MI:0915”(physical association)	0.560
UNC50	FITM2	psi-mi:“MI:0915”(physical association)	0.560
UNC50	GPR152	psi-mi:“MI:0915”(physical association)	0.560
KCNJ6	UNC50	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	UNC50	psi-mi:“MI:0915”(physical association)	0.560
UNC50	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): UNC50 (Two-hybrid), UNC50 (Affinity Capture-MS), UNC50 (Affinity Capture-MS), UNC50 (Synthetic Lethality), UNC50 (Two-hybrid), UNC50 (Two-hybrid), UNC50 (Two-hybrid), UNC50 (Two-hybrid), UNC50 (Two-hybrid), DARS2 (Two-hybrid), ELOVL4 (Two-hybrid), MTIF3 (Two-hybrid), FAM209A (Two-hybrid), ERGIC3 (Two-hybrid), FFAR2 (Two-hybrid)

ESM2 similar proteins: B6JWP7, F4JRE0, O13742, O55227, O64761, O74787, O94348, O94673, O95070, P32802, P36125, P53039, P53093, P87148, P87155, Q04562, Q09906, Q10045, Q10269, Q18695, Q1PE48, Q3T196, Q3ZBG6, Q4FZQ0, Q4KLL4, Q53HI1, Q54DD7, Q54ER8, Q54GD9, Q5RBL0, Q5RDY2, Q5U3G6, Q5U520, Q61ZW5, Q6DKM1, Q6DNA2, Q6GN58, Q6P301, Q6P6G5, Q6PC24

Diamond homologs: O55227, P36125, P87155, Q10045, Q3ZBG6, Q53HI1, Q54DD7, Q5U520, Q6DKM1, Q7ZUU1, Q9CQ61, Q9VHN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	1
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1167 predictions. Top by Δscore:

Variant	Effect	Δscore
2:98608633:G:T	donor_gain	1.0000
2:98608638:G:T	donor_gain	1.0000
2:98610021:T:G	donor_gain	1.0000
2:98610037:GTG:G	donor_gain	1.0000
2:98610773:A:AG	acceptor_gain	1.0000
2:98610774:G:GA	acceptor_gain	1.0000
2:98610774:GT:G	acceptor_gain	1.0000
2:98608633:G:GT	donor_gain	0.9900
2:98608638:G:GT	donor_gain	0.9900
2:98608884:G:GT	donor_gain	0.9900
2:98610021:T:TG	donor_gain	0.9900
2:98610039:GGT:G	donor_loss	0.9900
2:98610040:G:GG	donor_gain	0.9900
2:98608652:G:GA	donor_gain	0.9800
2:98608682:G:GA	donor_gain	0.9800
2:98609223:G:GT	donor_gain	0.9800
2:98610893:GTG:G	donor_gain	0.9800
2:98608651:T:TA	donor_gain	0.9700
2:98608677:G:GT	donor_gain	0.9700
2:98608880:A:T	donor_gain	0.9700
2:98609239:G:T	donor_gain	0.9700
2:98609751:TCTA:T	acceptor_loss	0.9700
2:98609752:CTAGG:C	acceptor_loss	0.9700
2:98609754:A:AG	acceptor_gain	0.9700
2:98609754:AGGA:A	acceptor_loss	0.9700
2:98609755:G:GG	acceptor_gain	0.9700
2:98609755:GGAA:G	acceptor_gain	0.9700
2:98610042:A:AG	donor_loss	0.9700
2:98608456:TGCA:T	donor_gain	0.9600
2:98608583:G:GT	donor_gain	0.9600

AlphaMissense

1681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:98609995:G:C	R79T	0.999
2:98609995:G:T	R79I	0.999
2:98610001:A:G	D81G	0.999
2:98610004:C:A	P82H	0.999
2:98610009:T:C	F84L	0.999
2:98610011:C:A	F84L	0.999
2:98610011:C:G	F84L	0.999
2:98616262:T:A	W153R	0.999
2:98616262:T:C	W153R	0.999
2:98616482:T:A	W198R	0.999
2:98616482:T:C	W198R	0.999
2:98609905:C:A	A49D	0.998
2:98609988:T:A	W77R	0.998
2:98609988:T:C	W77R	0.998
2:98609996:A:C	R79S	0.998
2:98609996:A:T	R79S	0.998
2:98609997:G:C	D80H	0.998
2:98610024:A:C	S89R	0.998
2:98610026:T:A	S89R	0.998
2:98610026:T:G	S89R	0.998
2:98616278:A:T	D158V	0.998
2:98616287:T:C	L161P	0.998
2:98616292:G:C	A163P	0.998
2:98616518:T:C	F210L	0.998
2:98616520:C:A	F210L	0.998
2:98616520:C:G	F210L	0.998
2:98616524:G:A	G212R	0.998
2:98616524:G:C	G212R	0.998
2:98616525:G:A	G212E	0.998
2:98609891:G:A	M44I	0.997

dbSNP variants (sampled 300 via entrez): RS1001333967 (2:98609550 G>A,C,T), RS1001531752 (2:98615124 G>A), RS1001707368 (2:98611435 T>G), RS1002355503 (2:98615711 C>G), RS1002356064 (2:98608993 G>T), RS1002578602 (2:98617174 A>G), RS1002708203 (2:98615418 C>T), RS1002735433 (2:98610687 G>A), RS1003089375 (2:98617418 G>T), RS1003276796 (2:98606788 C>G), RS1003854478 (2:98617781 C>T), RS1003898891 (2:98608463 G>A,C,T), RS1003928137 (2:98608210 A>C,G,T), RS1004414554 (2:98611465 G>C,T), RS1005502297 (2:98617658 T>C)

Disease associations

OMIM: gene MIM:617826 | disease phenotypes: MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis multiplex congenita	Moderate	Autosomal recessive
congenital myasthenic syndrome	Moderate	Autosomal recessive

Mondo (3): arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), congenital myasthenic syndrome (MONDO:0018940)

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

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006479_124	Diverticular disease	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Cyclosporine	decreases expression, decreases methylation	2
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
ICG 001	increases expression	1
bisphenol S	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Antimycin A	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3
NCT00872950	Not specified	APPROVED_FOR_MARKETING	3,4-Diaminopyridine Use in Lambert-Eaton Myasthenic Syndrome(LEMS) and Congenital Myasthenic Syndromes (CMS)
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01474980	Not specified	COMPLETED	Pregnancy Outcomes in Congenital Myasthenie Syndrome
NCT02012933	Not specified	NO_LONGER_AVAILABLE	3,4-Diaminopyridine for Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenia (CM)
NCT02189720	Not specified	APPROVED_FOR_MARKETING	Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome
NCT03062631	Not specified	NO_LONGER_AVAILABLE	Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia
NCT05408702	Not specified	COMPLETED	Exercise in Autoimmune Myasthenia Gravis and Myasthenic Syndromes
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06078553	Not specified	RECRUITING	A Natural History Study in Participants With Congenital Myasthenic Syndromes (CMS) Due to Mutations in DOK7, MUSK, AGRN, or LRP4