UNC5CL

Summary

UNC5CL (unc-5 family C-terminal like, HGNC:21203) is a protein-coding gene on chromosome 6p21.1, encoding UNC5C-like protein (Q8IV45). Inhibits NF-kappa-B-dependent transcription by impairing NF-kappa-B binding to its targets.

Enables peptidase activity. Acts upstream of or within positive regulation of JNK cascade and positive regulation of canonical NF-kappaB signal transduction. Located in centrosome; cytosol; and membrane.

Source: NCBI Gene 222643 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 95 total
• MANE Select transcript: NM_173561

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21203
Approved symbol	UNC5CL
Name	unc-5 family C-terminal like
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC34763, ZUD
Ensembl gene	ENSG00000124602
Ensembl biotype	protein_coding
OMIM	617464
Entrez	222643

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000244565, ENST00000373164, ENST00000470102, ENST00000714028

RefSeq mRNA: 1 — MANE Select: NM_173561 NM_173561

CCDS: CCDS4847

Canonical transcript exons

ENST00000244565 — 9 exons

Exon	Start	End
ENSE00001300678	41026895	41028595
ENSE00001422848	41039162	41039221
ENSE00003488000	41032036	41032137
ENSE00003647542	41030655	41030755
ENSE00003665687	41030388	41030501
ENSE00003890704	41031681	41031748
ENSE00003892117	41032884	41033146
ENSE00003895096	41034690	41035135
ENSE00003896222	41033881	41034181

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 97.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5658 / max 170.5132, expressed in 58 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73513	0.4934	45
73514	0.0679	30
73515	0.0045	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	97.44	gold quality
pancreatic ductal cell	CL:0002079	96.20	gold quality
kidney epithelium	UBERON:0004819	94.15	gold quality
ileal mucosa	UBERON:0000331	94.07	gold quality
duodenum	UBERON:0002114	92.52	gold quality
right lobe of liver	UBERON:0001114	92.13	gold quality
body of pancreas	UBERON:0001150	90.31	gold quality
jejunal mucosa	UBERON:0000399	90.27	gold quality
adult mammalian kidney	UBERON:0000082	88.77	gold quality
metanephros cortex	UBERON:0010533	88.61	gold quality
pancreas	UBERON:0001264	86.91	gold quality
pylorus	UBERON:0001166	86.42	gold quality
liver	UBERON:0002107	84.78	gold quality
body of stomach	UBERON:0001161	84.58	gold quality
gall bladder	UBERON:0002110	84.44	gold quality
kidney	UBERON:0002113	83.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.25	gold quality
islet of Langerhans	UBERON:0000006	82.94	gold quality
small intestine	UBERON:0002108	82.88	gold quality
cortex of kidney	UBERON:0001225	82.27	gold quality
stomach	UBERON:0000945	82.04	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.06	gold quality
tendon of biceps brachii	UBERON:0008188	79.19	silver quality
granulocyte	CL:0000094	78.31	gold quality
fundus of stomach	UBERON:0001160	77.89	gold quality
upper arm skin	UBERON:0004263	77.24	gold quality
oviduct epithelium	UBERON:0004804	77.12	gold quality
jejunum	UBERON:0002115	77.01	gold quality
metanephros	UBERON:0000081	76.20	gold quality
mucosa of stomach	UBERON:0001199	75.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting UNC5CL, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-3691-3P	97.90	65.97	791
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299

Literature-anchored findings (GeneRIF, showing 3)

• ZUD is an inhibitor of NF-kappaB activation and may provide an alternative regulatory mechanism for NF-kappaB-mediated transcription (PMID:14769797)
• The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. (PMID:22158417)
• rs2294693 near UNC5CL was significantly associated with Gastric non-cardia cancer risk (p=2.50x10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47x10(-2). (PMID:26129866)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Unc5cl	ENSMUSG00000043592
rattus_norvegicus	Unc5cl	ENSRNOG00000046601
drosophila_melanogaster	unc-5	FBGN0034013
caenorhabditis_elegans		WBGENE00006745

Paralogs (4): UNC5B (ENSG00000107731), UNC5A (ENSG00000113763), UNC5D (ENSG00000156687), UNC5C (ENSG00000182168)

Protein

Protein identifiers

UNC5C-like protein — Q8IV45 (reviewed: Q8IV45)

Alternative names: Protein unc-5 homolog C-like, ZU5 and death domain-containing protein

All UniProt accessions (3): A0AAQ5BHA7, H8YHX0, Q8IV45

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits NF-kappa-B-dependent transcription by impairing NF-kappa-B binding to its targets.

Subunit / interactions. Interacts with p65/RELA and NFKB1.

Subcellular location. Membrane. Cytoplasm.

Tissue specificity. Expressed in pancreas, liver and kidney.

Similarity. Belongs to the unc-5 family.

RefSeq proteins (1): NP_775832* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000906	ZU5_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR033772	UPA	Domain
IPR037936	UNC5A-D	Family

Pfam: PF00531, PF00791, PF17217

UniProt features (13 total): region of interest 3, topological domain 2, active site 2, domain 2, chain 1, sequence variant 1, transmembrane region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IV45-F1	80.18	0.57

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 (2): 227; 229

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_JNK_CASCADE, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOMF_PEPTIDASE_ACTIVITY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, WAMUNYOKOLI_OVARIAN_CANCER_LMP_UP, MIKKELSEN_ES_ICP_WITH_H3K4ME3, WHITFIELD_CELL_CYCLE_G2, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, BRUINS_UVC_RESPONSE_LATE, GOBP_NETRIN_ACTIVATED_SIGNALING_PATHWAY, TORCHIA_TARGETS_OF_EWSR1_FLI1_FUSION_UP

GO Biological Process (4): positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of JNK cascade (GO:0046330), signal transduction (GO:0007165), netrin-activated signaling pathway (GO:0038007)

GO Molecular Function (3): netrin receptor activity (GO:0005042), peptidase activity (GO:0008233), protein binding (GO:0005515)

GO Cellular Component (4): centrosome (GO:0005813), cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
transmembrane signaling receptor activity	1
netrin-activated signaling pathway	1
hydrolase activity	1
catalytic activity, acting on a protein	1
binding	1
centriole	1
microtubule organizing center	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC5CL	LRFN2	Q9ULH4	570
UNC5CL	PLCE1	Q9P212	516
UNC5CL	OR6K6	Q8NGW6	515
UNC5CL	DEFB121	Q5J5C9	471
UNC5CL	ZBTB20	Q9HC78	436
UNC5CL	SLC52A3	Q9NQ40	399
UNC5CL	PSCA	O43653	396
UNC5CL	TMC3	Q7Z5M5	395
UNC5CL	CCDC85A	Q96PX6	370
UNC5CL	PRKAA1	Q13131	367
UNC5CL	MMP20	O60882	362
UNC5CL	ENAM	Q9NRM1	361
UNC5CL	CEP63	Q96MT8	356
UNC5CL	MSX2	P35548	353
UNC5CL	PER2	O15055	353
UNC5CL	PER1	O15534	353

IntAct

24 interactions, top by confidence:

A	B	Type	Score
UNC5CL	CYSRT1	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	UNC5CL	psi-mi:“MI:0915”(physical association)	0.560
PGAM1	UNC5CL	psi-mi:“MI:0915”(physical association)	0.560
KRTAP13-2	UNC5CL	psi-mi:“MI:0915”(physical association)	0.560
UNC5CL	TOX2	psi-mi:“MI:0915”(physical association)	0.560
UNC5CL	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-1	UNC5CL	psi-mi:“MI:0915”(physical association)	0.560
UNC5CL	CHEK1	psi-mi:“MI:0914”(association)	0.350
AXDND1	SRP72	psi-mi:“MI:0914”(association)	0.350
UNC5CL	INSR	psi-mi:“MI:0914”(association)	0.350
UNC5CL	PGAM1	psi-mi:“MI:0915”(physical association)	0.000
UNC5CL	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.000
UNC5CL	ZMYND12	psi-mi:“MI:0915”(physical association)	0.000
UNC5CL	TOX2	psi-mi:“MI:0915”(physical association)	0.000
UNC5CL	KRTAP6-1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (33): BICD2 (Affinity Capture-MS), INSR (Affinity Capture-MS), NUMB (Affinity Capture-MS), LRRC41 (Affinity Capture-MS), KDM8 (Affinity Capture-MS), IGF1R (Affinity Capture-MS), NUMBL (Affinity Capture-MS), FLVCR1 (Affinity Capture-MS), CHORDC1 (Affinity Capture-MS), USP22 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), POM121 (Affinity Capture-MS), NFKB1 (Affinity Capture-Western), RELA (Affinity Capture-Western)

ESM2 similar proteins: A2VE78, A5PK16, A6QP29, B1AVH7, B5DFA1, C0HAC0, D2H0G5, D2HNY3, O15040, P31152, P41002, P51944, Q13615, Q2YDQ5, Q32NM1, Q3UMR0, Q400C9, Q5F479, Q5M9H0, Q5PQT2, Q5REW9, Q5RF77, Q5XGG5, Q69ZT1, Q6NYX6, Q6R653, Q6ZW76, Q7T0L6, Q7TNH6, Q80TI1, Q810L3, Q86XL3, Q8BVF9, Q8C2S5, Q8IV13, Q8IV45, Q8JZL1, Q8K296, Q8K4F8, Q8NFM7

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1523 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41028602:C:T	acceptor_gain	1.0000
6:41028602:CGAGG:C	acceptor_gain	1.0000
6:41028603:G:T	acceptor_gain	1.0000
6:41028606:G:C	acceptor_gain	1.0000
6:41028606:G:GC	acceptor_gain	1.0000
6:41030374:ACC:A	donor_gain	1.0000
6:41030375:CCC:C	donor_gain	1.0000
6:41030503:T:C	acceptor_gain	1.0000
6:41031679:A:AC	donor_gain	1.0000
6:41031679:ACAT:A	donor_gain	1.0000
6:41031680:C:CC	donor_gain	1.0000
6:41031680:CATC:C	donor_gain	1.0000
6:41031682:T:TA	donor_gain	1.0000
6:41039158:TTA:T	donor_loss	1.0000
6:41039159:TA:T	donor_loss	1.0000
6:41039160:A:AC	donor_gain	1.0000
6:41039160:A:T	donor_loss	1.0000
6:41039160:AC:A	donor_gain	1.0000
6:41039161:C:CA	donor_gain	1.0000
6:41039161:CC:C	donor_gain	1.0000
6:41039161:CCG:C	donor_gain	1.0000
6:41039161:CCGT:C	donor_gain	1.0000
6:41028596:C:CG	acceptor_loss	0.9900
6:41030375:CCCCT:C	donor_gain	0.9900
6:41030498:CAGC:C	acceptor_gain	0.9900
6:41030501:CC:C	acceptor_loss	0.9900
6:41030501:CCT:C	acceptor_gain	0.9900
6:41030502:C:CC	acceptor_gain	0.9900
6:41030502:CTT:C	acceptor_loss	0.9900
6:41030503:T:TC	acceptor_gain	0.9900

AlphaMissense

3360 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41030434:A:G	W430R	0.999
6:41030434:A:T	W430R	0.999
6:41032135:A:G	W318R	0.999
6:41032135:A:T	W318R	0.999
6:41034084:G:C	S161R	0.999
6:41034084:G:T	S161R	0.999
6:41034086:T:G	S161R	0.999
6:41030432:C:A	W430C	0.998
6:41030432:C:G	W430C	0.998
6:41031703:A:T	V366D	0.998
6:41032050:A:G	F346S	0.998
6:41033036:C:G	R266P	0.998
6:41033077:G:C	F252L	0.998
6:41033077:G:T	F252L	0.998
6:41033079:A:G	F252L	0.998
6:41028481:G:C	C483W	0.997
6:41030475:A:G	L416P	0.997
6:41032133:C:A	W318C	0.997
6:41032133:C:G	W318C	0.997
6:41033949:C:A	W206C	0.997
6:41033949:C:G	W206C	0.997
6:41028491:C:G	R480P	0.996
6:41030421:G:T	A434D	0.996
6:41033951:A:G	W206R	0.996
6:41033951:A:T	W206R	0.996
6:41032134:C:G	W318S	0.995
6:41032907:A:G	L309P	0.995
6:41033024:A:G	L270P	0.995
6:41033031:A:C	Y268D	0.995
6:41033037:G:T	R266S	0.995

dbSNP variants (sampled 300 via entrez): RS1000039207 (6:41039841 C>T), RS1000303208 (6:41030247 T>A,G), RS1000412179 (6:41039586 A>G), RS1000457588 (6:41036402 C>T), RS1000639136 (6:41031454 C>T), RS1000988142 (6:41034034 G>A), RS1001019051 (6:41041005 C>G), RS1001104450 (6:41028302 G>C,T), RS1001197670 (6:41037914 A>C), RS1001292337 (6:41036932 C>T), RS1001653372 (6:41031530 C>A,T), RS1002160230 (6:41031075 A>G), RS1002549619 (6:41032171 G>A), RS1002836031 (6:41026429 A>G), RS1002863123 (6:41031854 G>T)

Disease associations

OMIM: gene MIM:617464 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001089_11	Esophageal cancer	7.000000e-12
GCST003007_1	Non-cardia gastric cancer	3.000000e-08
GCST003010_4	Gastric cancer	7.000000e-08
GCST008971_77	Urate levels	1.000000e-10
GCST008972_8	Urate levels	8.000000e-11
GCST90012877_28	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-07
GCST90012877_29	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-12
GCST90012877_30	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-23

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009268	family history of Alzheimer’s disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
Aflatoxin B1	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
OTX015	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Hydrogen Peroxide	affects expression	1
Oxygen	increases expression	1
Phthalic Acids	decreases expression	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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