Cold-induced sweating syndrome 2

Summary

Cold-induced sweating syndrome 2 (MONDO:0012467) is a disease caused by CLCF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CLCF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cold-induced sweating syndrome 2
Mondo ID	MONDO:0012467
MeSH	C564791
OMIM	610313
DOID	DOID:0080330
UMLS	C1853198
MedGen	342816
GARD	0018277
Is cancer (heuristic)	no

Also known as: CISS2 · CLCF1 cold-induced sweating syndrome · cold-induced sweating syndrome 2 · cold-induced sweating syndrome caused by mutation in CLCF1 · cold-induced sweating syndrome type 2

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › cold-induced sweating syndrome - hyperthermia spectrum › cold-induced sweating syndrome › cold-induced sweating syndrome 2

Related subtypes (2): Cold-induced sweating syndrome 1, PERCHING syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
21503	NM_013246.3(CLCF1):c.46T>C (p.Cys16Arg)	CLCF1	Pathogenic	no assertion criteria provided
2930	NM_013246.3(CLCF1):c.321C>A (p.Tyr107Ter)	CLCF1	Pathogenic	no assertion criteria provided
2931	NM_013246.3(CLCF1):c.590G>T (p.Arg197Leu)	CLCF1	Pathogenic	no assertion criteria provided
39568	NM_013246.3(CLCF1):c.676T>C (p.Ter226Arg)	CLCF1	Pathogenic	no assertion criteria provided
548547	NM_013246.3(CLCF1):c.163C>T (p.Arg55Cys)	CLCF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CLCF1	Strong	Autosomal recessive	cold-induced sweating syndrome 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCF1	Orphanet:1545	Crisponi syndrome
CLCF1	Orphanet:157820	Cold-induced sweating syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLCF1	HGNC:17412	ENSG00000175505	Q9UBD9	Cardiotrophin-like cytokine factor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCF1	Cardiotrophin-like cytokine factor 1	In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCF1	Other/Unknown	no		4_helix_cytokine-like_core, PRF/CT

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCF1	187	ubiquitous	marker	left uterine tube, metanephros cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCF1	491

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCF1	Q9UBD9	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IL-6-type cytokine receptor ligand interactions	1	634.4×	0.002	CLCF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of isotype switching to IgE isotypes	1	4213.0×	0.003	CLCF1
positive regulation of astrocyte differentiation	1	1404.3×	0.004	CLCF1
cell surface receptor signaling pathway via STAT	1	561.7×	0.006	CLCF1
positive regulation of immunoglobulin production	1	481.5×	0.006	CLCF1
positive regulation of B cell proliferation	1	343.9×	0.006	CLCF1
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	CLCF1
B cell differentiation	1	218.9×	0.007	CLCF1
cytokine-mediated signaling pathway	1	130.6×	0.011	CLCF1
negative regulation of neuron apoptotic process	1	110.9×	0.011	CLCF1
cell surface receptor signaling pathway	1	64.1×	0.017	CLCF1
positive regulation of cell population proliferation	1	33.6×	0.030	CLCF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLCF1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.