CLCF1

Chr 11

cardiotrophin like cytokine factor 1

Also known as: BSF-3, BSF3, CISS2, CLC, NNT-1, NNT1, NR6

NCBI Gene: 23529 ENSG00000175505 UniProt: Q9UBD9

CLCF1 encodes cardiotrophin-like cytokine factor 1, which forms a heterodimeric neurotropic cytokine complex with CRLF1 that plays a crucial role in neuronal development and also stimulates B-cells by activating the gp130 receptor and Jak-STAT signaling pathway. Mutations cause cold-induced sweating syndrome 2, an autosomal recessive disorder characterized by profuse sweating after cold exposure along with congenital abnormalities of the head and spine. This condition typically presents in infancy with the distinctive cold-induced sweating response and associated craniofacial and spinal malformations.

ResearchSummary from RefSeq, UniProt

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.[provided by RefSeq, Oct 2009]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCrisponi/Cold-induced sweating syndrome 2

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.948

Z-score 2.83

OE 0.00 (0.00–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.12Z-score

OE missense 0.74 (0.63–0.86)

104 obs / 141.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.32)

0≤0.351.4

Missense OE?0.74 (0.63–0.86)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 0 / 9.3Missense obs/exp: 104 / 141.5Syn Z: 0.41

Background carrier burden — how many people carry a rare variant somewhere in CLCF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

254 rare PASS variants

Rare truncating (LoF)

1 in 640

47 rare PASS variants

Rare synonymous (reference)

1 in 570

126 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CLCF1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 270	1 in 2,300
South Asian	~43k	1 in 220	1 in 8,200
Remaining (unassigned)	~30k	1 in 160	≈ 1 in 14,000
European (Finnish)	~27k	1 in 3,000	≈ 1 in 27,000
Admixed American	~22k	1 in 260	1 in 550
African / African American	~21k	1 in 230	1 in 1,800
East Asian	~20k	1 in 180	≈ 1 in 14,000
Ashkenazi Jewish	~13k	1 in 1,500	none seen
Middle Eastern	~2,884	1 in 220	≈ 1 in 1,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓