CLCF1

Summary

CLCF1 (cardiotrophin like cytokine factor 1, HGNC:17412) is a protein-coding gene on chromosome 11q13.2, encoding Cardiotrophin-like cytokine factor 1 (Q9UBD9). Functions as a cytokine, either alone or by forming a stable complex with soluble CRLF1 or CNTFR.

This gene is a member of the glycoprotein (gp)130 cytokine family and encodes cardiotrophin-like cytokine factor 1 (CLCF1). CLCF1 forms a heterodimer complex with cytokine receptor-like factor 1 (CRLF1). This dimer competes with ciliary neurotrophic factor (CNTF) for binding to the ciliary neurotrophic factor receptor (CNTFR) complex, and activates the Jak-STAT signaling cascade. CLCF1 can be actively secreted from cells by forming a complex with soluble type I CRLF1 or soluble CNTFR. CLCF1 is a potent neurotrophic factor, B-cell stimulatory agent and neuroendocrine modulator of pituitary corticotroph function. Defects in CLCF1 cause cold-induced sweating syndrome 2 (CISS2). This syndrome is characterized by a profuse sweating after exposure to cold as well as congenital physical abnormalities of the head and spine. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 23529 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cold-induced sweating syndrome 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 85 total — 4 pathogenic
• GTEx eGene: eQTL in 8 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 34
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.33 (intermediate), LOEUF 0.73 (unconstrained)
• MANE Select transcript: NM_013246

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17412
Approved symbol	CLCF1
Name	cardiotrophin like cytokine factor 1
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	NNT1, BSF3, CLC, NR6, CISS2, BSF-3, NNT-1
Ensembl gene	ENSG00000175505
Ensembl biotype	protein_coding
OMIM	607672
Entrez	23529

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

MANE Select: ENST00000312438

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1

ENST00000312438, ENST00000533438, ENST00001040953, ENST00001144165

RefSeq mRNA: 2 — MANE Select: NM_013246 NM_001166212, NM_013246

CCDS: CCDS31617, CCDS53666

Canonical transcript exons

ENST00000312438 — 3 exons

Exon	Start	End
ENSE00001213782	67373524	67373598
ENSE00001337542	67364168	67365630
ENSE00003560147	67367460	67367626

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 89.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0714 / max 569.5814, expressed in 1429 samples.

Highest expression (Bgee): uterine tube, metanephros cortex, male germ line stem cell (sensu Vertebrata) in testis, body of uterus, gall bladder.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CLCF1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	2.0e-11	-0.48	11:67079548:A:C
Nerve Tibial	sqtl	2.2e-04	-0.55	11:66911909:G:A
Adipose Visceral Omentum	eqtl	4.7e-04	-0.16	11:67366129:G:A
Colon Transverse	eqtl	8.2e-03	-0.37	11:67778725:G:A
Whole Blood	eqtl	1.1e-02	-0.26	11:67615718:C:T
Testis	eqtl	1.3e-02	-0.52	11:67633828:C:A
Stomach	eqtl	2.0e-02	+0.48	11:67272815:C:G
Pancreas	eqtl	3.0e-02	-0.61	11:67421123:G:A
Cells EBV-transformed lymphocytes	eqtl	3.9e-02	-0.17	11:67589238:C:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
120905	10.5751	1222
120906	1.9125	816
120908	0.3571	156
120907	0.2092	99
120904	0.0175	2

Top tissues by expression

showing 100 of 268 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left uterine tube	UBERON:0001303	89.66	gold quality
metanephros cortex	UBERON:0010533	88.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.53	gold quality
body of uterus	UBERON:0009853	85.09	gold quality
gall bladder	UBERON:0002110	84.49	gold quality
cartilage tissue	UBERON:0002418	84.05	gold quality
mucosa of stomach	UBERON:0001199	82.99	gold quality
granulocyte	CL:0000094	82.80	gold quality
endocervix	UBERON:0000458	82.49	gold quality
right uterine tube	UBERON:0001302	82.20	gold quality
stromal cell of endometrium	CL:0002255	81.94	gold quality
omental fat pad	UBERON:0010414	81.91	gold quality
peritoneum	UBERON:0002358	81.87	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.68	gold quality
lower esophagus	UBERON:0013473	81.62	gold quality
ascending aorta	UBERON:0001496	81.50	gold quality
thoracic aorta	UBERON:0001515	81.47	gold quality
descending thoracic aorta	UBERON:0002345	81.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.91	gold quality
nerve	UBERON:0001021	80.79	gold quality
tibial nerve	UBERON:0001323	80.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.68	gold quality
right lobe of thyroid gland	UBERON:0001119	80.58	gold quality
left lobe of thyroid gland	UBERON:0001120	80.11	gold quality
aorta	UBERON:0000947	80.00	gold quality
minor salivary gland	UBERON:0001830	79.65	gold quality
body of stomach	UBERON:0001161	79.25	gold quality
thyroid gland	UBERON:0002046	79.21	gold quality
tongue squamous epithelium	UBERON:0006919	79.14	gold quality
tibial artery	UBERON:0007610	79.08	gold quality
popliteal artery	UBERON:0002250	79.05	gold quality
myometrium	UBERON:0001296	78.87	gold quality
left coronary artery	UBERON:0001626	78.47	gold quality
right atrium auricular region	UBERON:0006631	78.15	gold quality
upper lobe of left lung	UBERON:0008952	78.08	gold quality
right coronary artery	UBERON:0001625	78.03	gold quality
buccal mucosa cell	CL:0002336	77.75	silver quality
coronary artery	UBERON:0001621	77.63	gold quality
gluteal muscle	UBERON:0002000	77.59	gold quality
smooth muscle tissue	UBERON:0001135	77.40	gold quality
mouth mucosa	UBERON:0003729	77.36	gold quality
tendon of biceps brachii	UBERON:0008188	77.31	gold quality
cardiac atrium	UBERON:0002081	77.27	gold quality
ectocervix	UBERON:0012249	77.27	gold quality
upper lobe of lung	UBERON:0008948	77.26	gold quality
transverse colon	UBERON:0001157	77.18	gold quality
right ovary	UBERON:0002118	76.98	gold quality
esophagus	UBERON:0001043	76.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.71	gold quality
triceps brachii	UBERON:0001509	76.70	gold quality
spleen	UBERON:0002106	76.64	gold quality
decidua	UBERON:0002450	76.64	silver quality
left ovary	UBERON:0002119	76.41	gold quality
epithelial cell of pancreas	CL:0000083	76.34	silver quality
saliva-secreting gland	UBERON:0001044	75.95	gold quality
adenohypophysis	UBERON:0002196	75.84	gold quality
body of pancreas	UBERON:0001150	75.80	gold quality
stomach	UBERON:0000945	75.74	gold quality
lower esophagus mucosa	UBERON:0035834	75.24	gold quality
colon	UBERON:0001155	75.17	gold quality
uterus	UBERON:0000995	75.09	gold quality
adult mammalian kidney	UBERON:0000082	74.98	gold quality
cortex of kidney	UBERON:0001225	74.90	gold quality
pancreas	UBERON:0001264	74.89	gold quality
vagina	UBERON:0000996	74.82	gold quality
right lung	UBERON:0002167	74.67	gold quality
large intestine	UBERON:0000059	74.63	gold quality
palpebral conjunctiva	UBERON:0001812	74.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.15	gold quality
intestine	UBERON:0000160	74.05	gold quality
small intestine	UBERON:0002108	74.03	gold quality
metanephros	UBERON:0000081	73.80	gold quality
female reproductive system	UBERON:0000474	73.75	gold quality
pancreatic ductal cell	CL:0002079	73.61	silver quality
vermiform appendix	UBERON:0001154	73.59	gold quality
prostate gland	UBERON:0002367	73.58	gold quality
uterine cervix	UBERON:0000002	73.50	gold quality
adipose tissue	UBERON:0001013	73.47	gold quality
islet of Langerhans	UBERON:0000006	73.41	gold quality
cerebellar vermis	UBERON:0004720	73.30	silver quality
ovary	UBERON:0000992	73.24	gold quality
connective tissue	UBERON:0002384	73.19	gold quality
myocardium	UBERON:0002349	73.11	gold quality
left adrenal gland cortex	UBERON:0035825	73.02	gold quality
subcutaneous adipose tissue	UBERON:0002190	72.99	gold quality
heart	UBERON:0000948	72.98	gold quality
fallopian tube	UBERON:0003889	72.94	gold quality
esophagus mucosa	UBERON:0002469	72.88	gold quality
kidney	UBERON:0002113	72.69	gold quality
lymph node	UBERON:0000029	72.68	gold quality
heart left ventricle	UBERON:0002084	72.58	gold quality
left adrenal gland	UBERON:0001234	72.50	gold quality
leukocyte	CL:0000738	72.38	gold quality
caecum	UBERON:0001153	72.33	gold quality
cardiac ventricle	UBERON:0002082	72.21	gold quality
mucosa of paranasal sinus	UBERON:0005030	72.11	gold quality
monocyte	CL:0000576	71.95	gold quality
mononuclear cell	CL:0000842	71.80	gold quality
pituitary gland	UBERON:0000007	71.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 132 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	426.7	medium
Small intestine	tissue	39.1	not detected
Appendix	tissue	28.3	not detected
Duodenum	tissue	23.8	not detected
Smooth muscle	tissue	22.8	not detected
Urinary bladder	tissue	22.5	not detected
Urinary bladder	tissue	16.8	low
Gallbladder	tissue	16.6	low
Gallbladder	tissue	15.5	not detected
Stomach 1	tissue	14.7	not detected
Endometrium 1	tissue	13.2	low
Bone marrow	tissue	12.9	medium
Spleen	tissue	10.6	medium
Adipose tissue	tissue	10.6	low
Colon	tissue	9.6	not detected
Choroid plexus	tissue	8.5
Vagina	tissue	7.9	low
Smooth muscle	tissue	7.8	medium
Rectum	tissue	7.6	not detected
Pituitary gland	tissue	7.6
Appendix	tissue	7.5	low
Thymus	tissue	6.8
Fallopian tube	tissue	6.4	low
Pancreas	tissue	6.2	low
Lung	tissue	5.9	not detected
Hippocampus	tissue	5.7	low
Locus coeruleus	tissue	5.4
Nucleus accumbens	tissue	5.1
Lymph node	tissue	5.0	low
Cervix	tissue	4.8	low
Postcentral gyrus	tissue	4.6
Liver	tissue	4.5	not detected
Kidney	tissue	4.1	medium
Tonsil	tissue	4.1	medium
Placenta	tissue	4.0	low
Spinal cord	tissue	3.9
Lung	tissue	3.8	medium
Spleen	tissue	3.7	low
Thyroid gland	tissue	3.3	low
Adrenal gland	tissue	3.1	low
Stomach 1	tissue	3.0	medium
Ovary	tissue	3.0	low
Prostate	tissue	2.5	not detected
Liver	tissue	2.3	low
Heart muscle	tissue	2.2	medium
Colon	tissue	2.1	low
Adipose tissue	tissue	1.9	not detected
Tongue	tissue	1.8
Seminal vesicle	tissue	1.7	low
Esophagus	tissue	1.7	not detected
Lymph node	tissue	1.6	medium
Fallopian tube	tissue	1.6	not detected
Rectum	tissue	1.6	low
Skin 1	tissue	1.5	low
Medulla oblongata	tissue	1.5
Skin 1	tissue	1.4	not detected
Breast	tissue	1.4	medium
Testis	tissue	1.4	low
Superior colliculi	tissue	1.4
Placenta	tissue	1.3	not detected

Brain sub-regions (HPA Brain Atlas): detected in 209; highest nTPM — Blood vessel (12.6), Anterior thalamic nucleus, ventral (9.6), Precentral gyrus (9.2), Area postrema (8.9), Corticomedial amygdala (8.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CLCF1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 82 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3150A-3P	99.76	64.44	1640

Functional genomics

gnomAD constraint: pLI 0.332, LOEUF 0.734, missense Z 1.43 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000312438 — one region, missense o/e 0.82. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• activation of the Jak-STAT cascade is essential for corticotroph NNT-1/BSF-3 signaling. (PMID:12639901)
• Structural and docking interaction studies showed that the R197L substitution destabilized the contact site between CLC and CNTFRalpha. (PMID:16782820)
• Ciliary neurotrophic factor, cardiotrophin-like cytokine, and neuropoietin share a conserved binding site on the ciliary neurotrophic factor receptor alpha chain (PMID:18728012)
• albuminuria in focal segmental glomerulosclerosis is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex. (PMID:25843671)
• Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders. (PMID:26198769)
• CLF-1, based on its binding site for CLC and on two additional and independent sites for CNTFRalpha and sorLA, is a key player in CLC and CNTFRalpha signaling and turnover. (PMID:26858303)
• Very low-density lipoproteins (VLDL)- and LDL-CLCF1 binding was confirmed using proximity and ligand blots assays. CLCF1-induced STAT3 phosphorylation was significantly reduced when the cytokine was complexed with VLDL. (PMID:29507344)
• Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts. (PMID:31497877)
• we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for lung adenocarcinoma and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment. (PMID:31700175)
• Association of cardiotrophin-like cytokine factor 1 levels in peripheral blood mononuclear cells with bone mineral density and osteoporosis in postmenopausal women. (PMID:33430863)
• Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-kappaB signaling pathway. (PMID:34364014)
• CRLF1 and CLCF1 in Development, Health and Disease. (PMID:35055176)
• CLCF1 Is a Novel Potential Immune-Related Target With Predictive Value for Prognosis and Immunotherapy Response in Glioma. (PMID:35265072)
• Intrahepatic paracrine signaling by cardiotrophin-like cytokine factor 1 ameliorates diet-induced NASH in mice. (PMID:35950514)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcf1	ENSDARG00000076140
mus_musculus	Clcf1	ENSMUSG00000040663
rattus_norvegicus	Clcf1	ENSRNOG00000018752

Paralogs (1): CTF1 (ENSG00000150281)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1930088) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased bone mineral density	1
decreased leukocyte cell number	1
abnormal facial motor nucleus morphology	1
decreased motor neuron number	1
decreased body weight	1
absent suckling reflex	1
prolonged QT interval	1
abnormal nervous system physiology	1
increased bone mineral content	1
postnatal lethality, complete penetrance	1
preweaning lethality, complete penetrance	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ANKRD13D	protein-coding	338692
SSH3	protein-coding	54961
PPP1CA	protein-coding	5499
POLD4	protein-coding	57804
RAD9A	protein-coding	5883
TBC1D10C	protein-coding	374403
CARNS1	protein-coding	57571

Protein

Protein identifiers

Cardiotrophin-like cytokine factor 1 — Q9UBD9 (reviewed: Q9UBD9)

Alternative names: B-cell-stimulating factor 3, Cardiotrophin-like cytokine, Novel neurotrophin-1

All UniProt accessions (1): Q9UBD9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a cytokine, either alone or by forming a stable complex with soluble CRLF1 or CNTFR. Binds to CNTFR complex (CNTFR, IL6ST/gp130, LIFR) or can signal via trans-signaling using soluble CNTFR subunits. Mechanistically, ligand binding to CNTFR, induces dimerization of the IL6ST/gp130 and LIFR, which activates JAK tyrosine kinases (JAK1 or JAK2 and to lesser extent TYK2) bound to their intracellular domains. These kinases subsequently phosphorylate IL6ST/gp130 and LIFR. The tyrosine phosphorylated signaling receptors serve in turn as docking sites for recruitment and activation of signal transducer and activators of transcription (STAT3 and to lesser extent STAT1). Moreover, CLCF1/CLF heterodimer induces tyrosine phosphorylation of PTPN11, that associates with IL6ST/gp130-LIFR, which in turn recruits PIK3 protein kinase followed by AKT protein phosphorylation. Participates in the survival of embryonic motor neurons. Also stimulates B-cells.

Subunit / interactions. Homodimer. Forms a heterotetrameric complex with CRLF1/CLF-1; this complex is a ligand of the ciliary neurotrophic factor (CNTF) receptor complex through CLCF1 and CNTFR binding. The CRLF1-CLCF1 heterodimer interacts with SORL1 (via Vps10p domain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety. The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also interacts with SORL1; this interaction may promote internalization and lysosomal degradation. Forms a complex with CNTFR, LFR and IL6ST.

Subcellular location. Secreted.

Tissue specificity. Expressed predominantly in lymph nodes, spleen, peripheral blood lymphocytes, bone marrow, and fetal liver.

Disease relevance. Crisponi/Cold-induced sweating syndrome 2 (CISS2) [MIM:610313] An autosomal recessive disorder characterized by profuse sweating induced by cool surroundings (temperatures of 7 to 18 degrees Celsius). Patients manifest, in the neonatal period, orofacial weakness with impaired sucking and swallowing, resulting in poor feeding. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. These features are referred to as Crisponi syndrome and can result in early death in infancy. Patients who survive into childhood have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Additional abnormalities include a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend the elbows and kyphoscoliosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. At the structural level composed of a canonical four-helix bundle structure in which four major helices (termed helices A to D) are linked by three loops (termed AB, BC, and CD loops), as well as three conserved receptor binding epitopes (termed sites 1 to 3). Sites 2 and 3 bind to IL6ST/gp130 and LIFR, respectively, while site 1 is occupied by CNTFR. CLCF1 sites 2 and 3 are engaged by two CRLF1 molecules in the heterodimeric complex. CLCF1 site 1 is captured by the elbow region of CNTFR and CLCF1 also binds to LIFR D3 to form the site 3.

Similarity. Belongs to the IL-6 superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBD9-1	1	yes
Q9UBD9-2	2

RefSeq proteins (2): NP_001159684, NP_037378* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR010681	PRF/CT	Family

Pfam: PF06875

UniProt features (17 total): helix 8, strand 2, sequence conflict 2, signal peptide 1, chain 1, glycosylation site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
8D7H	Cryo-EM structure of human CLCF1 in complex with CRLF1 and CNTFR alpha	ELECTRON MICROSCOPY	3.4
8D7R	Cryo-EM structure of human CLCF1 signaling complex: model containing the interaction core …	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBD9-F1	82.59	0.60

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

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

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	29

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-6788467	IL-6-type cytokine receptor ligand interactions	curated
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-6783589	Interleukin-6 family signaling	—
R-HSA-449147	Signaling by Interleukins	—

MSigDB gene sets: 516 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, FXR_IR1_Q6, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MYOGENIN_Q6, GOBP_TOLERANCE_INDUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GCANCTGNY_MYOD_Q6

GO Biological Process (11): positive regulation of immunoglobulin production (GO:0002639), cell surface receptor signaling pathway (GO:0007166), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), B cell differentiation (GO:0030183), positive regulation of B cell proliferation (GO:0030890), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of isotype switching to IgE isotypes (GO:0048295), positive regulation of astrocyte differentiation (GO:0048711), cell surface receptor signaling pathway via STAT (GO:0097696)

GO Molecular Function (6): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), ciliary neurotrophic factor receptor binding (GO:0005127), growth factor activity (GO:0008083), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (3): extracellular region (GO:0005576), CRLF-CLCF1 complex (GO:0097058), CNTFR-CLCF1 complex (GO:0097059)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Interleukin-6 family signaling	1
Immune System	1
Cytokine Signaling in Immune system	1
Signaling by Interleukins	1

GO top-level categories

33 GO namespaces:

Category	Terms
signal transduction	2
cell surface receptor signaling pathway	2
receptor ligand activity	2
extracellular protein-containing complex	2
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
cell surface receptor signaling pathway via STAT	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular response to cytokine stimulus	1
lymphocyte differentiation	1
B cell activation	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
positive regulation of isotype switching	1
isotype switching to IgE isotypes	1
regulation of isotype switching to IgE isotypes	1
positive regulation of glial cell differentiation	1
astrocyte differentiation	1
regulation of astrocyte differentiation	1
protein binding	1
cytokine receptor binding	1
binding	1
signaling receptor binding	1
signaling receptor activator activity	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway via JAK-STAT	BP	direct assay
cell surface receptor signaling pathway via STAT	BP	direct assay
cytokine-mediated signaling pathway	BP	direct assay
negative regulation of neuron apoptotic process	BP	direct assay
positive regulation of cell population proliferation	BP	direct assay
CNTFR-CLCF1 complex	CC	direct assay
CRLF-CLCF1 complex	CC	direct assay
extracellular region	CC	direct assay
ciliary neurotrophic factor receptor binding	MF	direct assay
cytokine activity	MF	direct assay
signaling receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 452 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCF1	CRLF1	O75462	965
CLCF1	CTF1	Q16619	838
CLCF1	CNTF	P26441	817
CLCF1	CNTFR	P26992	817
CLCF1	LIFR	P42702	734
CLCF1	IL6ST	P40189	609
CLCF1	REX1BD	Q96EN9	599
CLCF1	OSM	P13725	571
CLCF1	IL11	P20809	549
CLCF1	LIF	P15018	492
CLCF1	TGFB1	P01137	476
CLCF1	OSMR	Q99650	476
CLCF1	CXCL6	P80162	463
CLCF1	SLC10A6	Q3KNW5	444
CLCF1	IL6	P05231	441

IntAct

Human interaction partners of CLCF1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
CRLF1	physical association	0.770	5
APOE	physical association	0.520	3
CNTFR	physical association	0.490	2

BioGRID (17 interactions; top human partners by supporting records): CNTFR (Affinity Capture-Western; 2 records), AGRN (Affinity Capture-MS), CRLF1 (Affinity Capture-Western), FBXL7 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-RNA), KRT17 (Affinity Capture-MS), PARK7 (Affinity Capture-MS), PROK1 (Affinity Capture-MS), S100A1 (Reconstituted Complex), S100A6 (Reconstituted Complex), S100P (Reconstituted Complex), SETD3 (Affinity Capture-MS), VCP (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
CLCF1	up-regulates	IL6ST	binding
CLCF1	up-regulates	CNTFR	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
CLC-CLF-CNTFR complex	3	CLCF1, CNTFR, CRLF1

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CNTFR;LIFR;IL6ST	ligand

Disease & clinical

Genetic variants

Variant evidence for CLCF1: 85 ClinVar records (4 pathogenic / likely pathogenic); 16 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	52
Likely benign	14
Benign	6

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2930	NM_013246.3(CLCF1):c.321C>A (p.Tyr107Ter)	Pathogenic	no assertion criteria provided	1
2931	NM_013246.3(CLCF1):c.590G>T (p.Arg197Leu)	Pathogenic	no assertion criteria provided	1
21503	NM_013246.3(CLCF1):c.46T>C (p.Cys16Arg)	Pathogenic	no assertion criteria provided	1
39568	NM_013246.3(CLCF1):c.676T>C (p.Ter226Arg)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CLCF1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 833):

Position(s)	Effect	Δscore	Sites
19:39731506–39731507	acceptor_loss	1.0000	5
19:39734293	donor_gain	1.0000
11:67367458–67367459	donor_loss	0.9900	5
11:67373522–67373523	donor_loss	0.9900	5
19:39731506	acceptor_loss	0.9900
19:39734281–39734282	donor_loss	0.9900	5
19:39734421	acceptor_gain	0.9900
19:39735892	acceptor_gain	0.9900
19:39737932	donor_gain	0.9900
19:39737933	donor_loss	0.9900

AlphaMissense

565 missense substitutions predicted likely pathogenic (of 1,444 scored), across 136 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D201	8	0.993	0.998
F69	8	0.989	0.999
F74	8	0.984	0.999
F202	8	0.976	0.998
N106	8	0.970	0.999
F178	8	0.970	0.998
F136	8	0.944	0.988
D45	8	0.835	0.946
W194	7	0.992	0.997
W94	7	0.991	0.998
F185	7	0.988	0.997
W186	7	0.963	0.984
E190	7	0.947	0.990
E51	7	0.908	0.980
W196	7	0.907	0.972
D99	7	0.903	0.952
M151	7	0.897	0.966
S139	7	0.875	0.990
H52	7	0.792	0.946
D184	7	0.765	0.906

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Rectum Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (validation)	favorable	0.000109
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000205
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000603

Disease associations

OMIM: gene MIM:607672 | disease phenotypes: MIM:610313

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
cold-induced sweating syndrome 2	Strong	Autosomal recessive
Cold-induced sweating syndrome 1	Supportive	Autosomal recessive
cold-induced sweating syndrome	Supportive	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
Arthrogryposis	amber
Fetal anomalies	amber

Mondo (3): cold-induced sweating syndrome 2 (MONDO:0012467), Cold-induced sweating syndrome 1 (MONDO:0010091), cold-induced sweating syndrome (MONDO:0015526)

Orphanet (1): Cold-induced sweating syndrome (Orphanet:157820)

HPO phenotypes

34 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000293	Full cheeks
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000411	Protruding ear
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000966	Hypohidrosis
HP:0000975	Hyperhidrosis
HP:0001250	Seizure
HP:0001276	Hypertonia
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001377	Limited elbow extension
HP:0001522	Death in infancy
HP:0001645	Sudden cardiac death
HP:0002047	Malignant hyperthermia
HP:0002093	Respiratory insufficiency
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0002938	Lumbar hyperlordosis
HP:0002944	Thoracolumbar scoliosis
HP:0002967	Cubitus valgus
HP:0004691	2-3 toe syndactyly
HP:0007141	Sensorimotor neuropathy
HP:0011968	Feeding difficulties
HP:0025278	Cold-induced sweating
HP:0030084	Clinodactyly
HP:0030319	Weakness of facial musculature
HP:0100490	Camptodactyly of finger
HP:0100543	Cognitive impairment
HP:0100729	Large face

GWAS associations

16 associations:

Study	Trait	p-value
GCST90002381_192	Eosinophil count	9e-134
GCST90002382_436	Eosinophil percentage of white cells	3e-129
GCST004606_155	Eosinophil count	6e-58
GCST004600_109	Eosinophil percentage of white cells	4e-53
GCST004617_111	Eosinophil percentage of granulocytes	2e-47
GCST007294_121	Body fat distribution (trunk fat ratio)	1e-35
GCST004623_61	Neutrophil percentage of granulocytes	2e-33
GCST007294_155	Body fat distribution (trunk fat ratio)	8e-28
GCST007295_118	Body fat distribution (leg fat ratio)	1e-25
GCST007295_76	Body fat distribution (leg fat ratio)	1e-21
GCST90002380_118	Basophil percentage of white cells	4e-18
GCST90002379_53	Basophil count	4e-13
GCST005975_3	Eosinophil count	1e-12
GCST90002380_119	Basophil percentage of white cells	3e-11
GCST007293_83	Body fat distribution (arm fat ratio)	9e-8
GCST001851_5	Schizophrenia	2e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0004341	body fat distribution
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C536214	Crisponi syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
Estradiol	affects binding, decreases expression, affects cotreatment, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Resveratrol	decreases expression, affects cotreatment	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Nickel	increases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
GSK-J4	decreases expression	1
Glupearl 19S	increases expression	1
TL8-506	increases expression, affects cotreatment	1
lead acetate	increases expression	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
cetrorelix	decreases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
NSC668394	increases expression	1
Temozolomide	decreases expression	1
Decitabine	increases expression	1
Leflunomide	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_ZL84	UKMi002-A	Induced pluripotent stem cell	Male
CVCL_ZL85	UKMi002-B	Induced pluripotent stem cell	Male
CVCL_ZL86	UKMi002-C	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.