CRLF1

Summary

CRLF1 (cytokine receptor like factor 1, HGNC:2364) is a protein-coding gene on chromosome 19p12, encoding Cytokine receptor-like factor 1 (O75462). In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development.

This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells. Mutations in this gene result in Crisponi syndrome and cold-induced sweating syndrome.

Source: NCBI Gene 9244 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Cold-induced sweating syndrome 1 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 241 total — 19 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 58
• MANE Select transcript: NM_004750

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2364
Approved symbol	CRLF1
Name	cytokine receptor like factor 1
Location	19p12
Locus type	gene with protein product
Status	Approved
Aliases	CLF-1, CLF, CISS, CISS1
Ensembl gene	ENSG00000006016
Ensembl biotype	protein_coding
OMIM	604237
Entrez	9244

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000392386, ENST00000593286, ENST00000594325, ENST00000596360, ENST00000597131, ENST00000684169, ENST00000928241, ENST00000971858, ENST00000971859, ENST00000971860

RefSeq mRNA: 1 — MANE Select: NM_004750 NM_004750

CCDS: CCDS32962

Canonical transcript exons

ENST00000392386 — 9 exons

Exon	Start	End
ENSE00000691094	18599565	18599846
ENSE00000691095	18598772	18598901
ENSE00000691096	18598432	18598601
ENSE00000691097	18596892	18597049
ENSE00000691098	18596622	18596790
ENSE00000691099	18594247	18594434
ENSE00000866209	18594065	18594107
ENSE00001113507	18606542	18606799
ENSE00003516125	18593237	18593579

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.2791 / max 2361.9798, expressed in 942 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180040	24.6345	861
180041	3.9016	583
180037	0.6083	148
180035	0.0883	49
180036	0.0464	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.37	gold quality
popliteal artery	UBERON:0002250	99.10	gold quality
tibial artery	UBERON:0007610	99.10	gold quality
left coronary artery	UBERON:0001626	98.08	gold quality
aorta	UBERON:0000947	97.73	gold quality
coronary artery	UBERON:0001621	96.74	gold quality
thoracic aorta	UBERON:0001515	96.20	gold quality
ascending aorta	UBERON:0001496	96.16	gold quality
right lobe of thyroid gland	UBERON:0001119	95.04	gold quality
decidua	UBERON:0002450	94.65	gold quality
left lobe of thyroid gland	UBERON:0001120	94.42	gold quality
descending thoracic aorta	UBERON:0002345	94.42	gold quality
right frontal lobe	UBERON:0002810	93.94	gold quality
right atrium auricular region	UBERON:0006631	93.32	gold quality
nucleus accumbens	UBERON:0001882	92.97	gold quality
tibial nerve	UBERON:0001323	92.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.41	gold quality
thyroid gland	UBERON:0002046	91.73	gold quality
anterior cingulate cortex	UBERON:0009835	91.16	gold quality
cingulate cortex	UBERON:0003027	91.15	gold quality
mucosa of stomach	UBERON:0001199	90.92	gold quality
skin of leg	UBERON:0001511	90.89	gold quality
cardiac atrium	UBERON:0002081	90.02	gold quality
prefrontal cortex	UBERON:0000451	89.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.53	gold quality
left adrenal gland cortex	UBERON:0035825	89.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.28	gold quality
skin of abdomen	UBERON:0001416	89.05	gold quality
caudate nucleus	UBERON:0001873	88.99	gold quality
right adrenal gland cortex	UBERON:0035827	88.76	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	730.44
E-MTAB-8221	yes	600.63
E-ANND-3	yes	17.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PLAG1

miRNA regulators (miRDB)

11 targeting CRLF1, 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-8485	100.00	77.57	4731
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-7705	98.69	67.47	543
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-6841-5P	97.19	67.29	409
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-7976	95.75	65.67	1186
HSA-MIR-874-3P	95.02	65.66	806

Literature-anchored findings (GeneRIF, showing 20)

• Our data suggest that the CRLF1/CLC complex disrupts cartilage homeostasis and promotes the progress of OA by enhancing the proliferation of chondrocytes and suppressing the production of cartilage matrix (PMID:19921088)
• CRLF1 mutations showed that phenotypic severity of the two disorders: Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. (PMID:21326283)
• In idiopathic pulmonary fibrosis, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung. (PMID:22429962)
• Data indicate that CRLF1 serves its protective role by a cell autonomous mechanism that is independent of the gp130/JAK signaling pathway. (PMID:23818941)
• The mutation detected in CRLF1 has not been described in patients with CISS1, but in one with CS. These data seem to support the theory that CS and CISS1 are variants of the same disorder. (PMID:24008591)
• Article reports 11 novel mutations in CRLF1 expanding the mutational spectrum of CRLF1 in the Crisponi/cold-induced sweating type 1 syndrome to a total of 35 variants. (PMID:24488861)
• we show in this series of 12 patients from four families, all previously unpublished, that the homogeneity of the recently described c.983dupG (p.Ser328Argfs *2) mutation in CRLF1 was associated with a highly variable degree of severity, and that the phenotype significantly overlaps with the recently described COG6-related anhidrosis syndrome (MIM#615328 (PMID:26804344)
• 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)
• From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1) related symptoms are missing. (PMID:27976805)
• These results suggest that CRLF1 enhances cell proliferation and metastasis in PTC and thus may therefore be a potential therapeutic target for papillary thyroid carcinoma . (PMID:29515111)
• Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts. (PMID:31497877)
• CRLF1-MYH9 Interaction Regulates Proliferation and Metastasis of Papillary Thyroid Carcinoma Through the ERK/ETV4 Axis. (PMID:32982961)
• Three new cases of Crisponi /cold induced sweating syndrome (CS/CISS1) in Turkish families. (PMID:33910095)
• CRLF1 and CLCF1 in Development, Health and Disease. (PMID:35055176)
• Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey. (PMID:35699517)
• Novel Mutations in CRLF1: Case Reports with Crisponi Syndrome. (PMID:35984556)
• Long non-coding RNA MIR22HG suppresses the chondrogenic differentiation of human adipose-derived stem cells by interacting with CTCF to upregulate CRLF1. (PMID:37910254)
• Identification and validation of CRLF1 and NRG1 as immune-related signatures in hypertrophic scar. (PMID:38262564)
• ENO1 regulates IL-1beta-induced chondrocyte inflammation, apoptosis and matrix degradation possibly through the potential binding to CRLF1. (PMID:39116531)
• CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer. (PMID:39256356)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Crlf1	ENSMUSG00000007888
rattus_norvegicus	Crlf1	ENSRNOG00000020030

Paralogs (23): IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Cytokine receptor-like factor 1 — O75462 (reviewed: O75462)

Alternative names: Cytokine-like factor 1, ZcytoR5

All UniProt accessions (3): O75462, A0A804HI12, M0QZL6

UniProt curated annotations — full annotation on UniProt →

Function. In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development. May also play a regulatory role in the immune system.

Subunit / interactions. Forms covalent di- and tetramers. Forms a heteromeric complex with cardiotrophin-like cytokine CLCF1/CLC; the CRLF1-CLCF1 complex is a ligand for the ciliary neurotrophic factor receptor/CNTFR. The CRLF1-CLCF1 heterodimer binds SORL1 (via N-terminal ectodomain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety. The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also binds SORL1.

Subcellular location. Secreted.

Tissue specificity. Highest levels of expression observed in spleen, thymus, lymph node, appendix, bone marrow, stomach, placenta, heart, thyroid and ovary. Strongly expressed also in fetal lung.

Disease relevance. Crisponi/Cold-induced sweating syndrome 1 (CISS1) [MIM:272430] 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. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

Induction. Up-regulated in fibroblast primary cell cultures under stimulation by IFNG/IFN-gamma, TNF and IL6/interleukin-6.

Similarity. Belongs to the type I cytokine receptor family. Type 3 subfamily.

RefSeq proteins (1): NP_004741* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015152	Growth/epo_recpt_lig-bind	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050379	Type-I_Cytokine_Rcpt	Family

Pfam: PF00041, PF09067

Enzyme classification (BRENDA):

• EC 1.1.1.105 — all-trans-retinol dehydrogenase (NAD+) (BRENDA: 12 organisms, 80 substrates, 15 inhibitors, 31 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ALL-TRANS-RETINOL	—	6
NADH	0.011–0.224	6
ALL-TRANS-RETINAL	0.0018–0.57	5
NAD+	0.0002–0.46	3
11-CIS-RETINOL	0.0001–0.086	2
9-CIS-RETINOL	0.0022	1
ALL-TRANS RETINAL	0.0005	1
ALL-TRANS-RETINALDEHYDE	0.0005	1
ANDROSTERONE	0.0002	1
NADP+	0.027	1
NADPH	0.0015	1
RETINOL	0.12	1
RETINOL BOUND TO CELLULAR RETINOL BINDING PROTEI	0.0027	1

UniProt features (62 total): strand 26, sequence variant 15, glycosylation site 6, domain 3, disulfide bond 2, helix 2, region of interest 2, signal peptide 1, chain 1, sequence conflict 1, turn 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8D7H	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75462-F1	81.15	0.56

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 (1): 219

Disulfide bonds (2): 143–153, 184–195

Glycosylation sites (6): 104, 140, 168, 292, 382, 92

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6788467	IL-6-type cytokine receptor ligand interactions
R-HSA-9020956	Interleukin-27 signaling

MSigDB gene sets: 289 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GCANCTGNY_MYOD_Q6, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, SMID_BREAST_CANCER_RELAPSE_IN_LIVER_UP, GOCC_CELL_SURFACE, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GGGTGGRR_PAX4_03

GO Biological Process (6): ureteric bud development (GO:0001657), positive regulation of cell population proliferation (GO:0008284), cytokine-mediated signaling pathway (GO:0019221), negative regulation of neuron apoptotic process (GO:0043524), cell surface receptor signaling pathway via STAT (GO:0097696), negative regulation of motor neuron apoptotic process (GO:2000672)

GO Molecular Function (5): cytokine receptor activity (GO:0004896), cytokine binding (GO:0019955), cytokine activity (GO:0005125), ciliary neurotrophic factor receptor binding (GO:0005127), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), external side of plasma membrane (GO:0009897), signaling receptor complex (GO:0043235), CRLF-CLCF1 complex (GO:0097058)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Interleukin-6 family signaling	1
Interleukin-12 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	2
cellular anatomical structure	2
mesonephric tubule development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular response to cytokine stimulus	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
negative regulation of neuron apoptotic process	1
motor neuron apoptotic process	1
regulation of motor neuron apoptotic process	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
cytokine binding	1
immune receptor activity	1
protein binding	1
receptor ligand activity	1
cytokine receptor binding	1
binding	1
cytoplasm	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRLF1	CLCF1	Q9UBD9	997
CRLF1	REX1BD	Q96EN9	829
CRLF1	IL27	Q8NEV9	766
CRLF1	CNTF	P26441	725
CRLF1	CNTFR	P26992	601
CRLF1	IL6R	P08887	530
CRLF1	FN1	P02751	509
CRLF1	LIFR	P42702	492
CRLF1	IL12A	P29459	461
CRLF1	IL27RA	Q6UWB1	424
CRLF1	FGFR1	P11362	411
CRLF1	RAX2	Q96IS3	405
CRLF1	ICAM1	P05362	391
CRLF1	KLHL7	Q8IXQ5	374
CRLF1	TLR9	Q9NR96	373

IntAct

50 interactions, top by confidence:

A	B	Type	Score
CLCF1	CRLF1	psi-mi:“MI:0915”(physical association)	0.770
CRLF1	CLCF1	psi-mi:“MI:0407”(direct interaction)	0.770
CRLF1	CNTFR	psi-mi:“MI:0407”(direct interaction)	0.610
CRLF1	CNTFR	psi-mi:“MI:0915”(physical association)	0.610
CRLF1	SORL1	psi-mi:“MI:0407”(direct interaction)	0.540
SORL1	CRLF1	psi-mi:“MI:0915”(physical association)	0.540
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
IL27	CRLF1	psi-mi:“MI:0915”(physical association)	0.400
CRLF1		psi-mi:“MI:0915”(physical association)	0.400
CRLF1	Cntfr	psi-mi:“MI:0915”(physical association)	0.400
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
KLK1	CRLF1	psi-mi:“MI:0914”(association)	0.350
MFAP4	CRLF1	psi-mi:“MI:0914”(association)	0.350
HSPA5	CRLF1	psi-mi:“MI:0914”(association)	0.350
CRLF1	PRSS23	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BRICD5	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LCN6	POTEF	psi-mi:“MI:0914”(association)	0.350
IGLL5	POTEF	psi-mi:“MI:0914”(association)	0.350
ISLR		psi-mi:“MI:0914”(association)	0.350

BioGRID (73): CRLF1 (Affinity Capture-RNA), CRLF1 (Affinity Capture-RNA), CRLF1 (Affinity Capture-RNA), CRLF1 (Affinity Capture-MS), EGFL7 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), CRLF1 (Affinity Capture-MS), PRSS23 (Affinity Capture-MS), CRLF1 (Affinity Capture-MS), CTF1 (Affinity Capture-MS), PTPRS (Affinity Capture-MS), NGLY1 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), CRLF1 (Affinity Capture-MS), GANAB (Affinity Capture-MS)

ESM2 similar proteins: A0JNA2, A2RRU4, A6QM06, C0HL12, D3ZTD8, O14514, O54693, O60241, O60242, O75077, O75462, P08138, P97260, Q0GA42, Q13591, Q29RN8, Q3TMX7, Q3UHD1, Q4V7F2, Q4V9Z5, Q53EL9, Q5R7Y0, Q5VXM1, Q62217, Q6GQT6, Q6UXD5, Q6ZRP7, Q7TSK2, Q7TSQ1, Q7TT36, Q80ZF8, Q8BQC3, Q8BQH6, Q8CGM1, Q8IVU1, Q8IWK6, Q91XD7, Q924S4, Q92838, Q96MU8

Diamond homologs: O46561, O46600, O75462, P05710, P10912, P14787, P16310, P16471, P16882, P19756, P19941, P79108, P79194, Q02092, Q04594, Q08501, Q28172, Q28235, Q28575, Q6JTA8, Q90374, Q90375, Q91094, Q91513, Q95JF2, Q95ML5, Q9JI97, Q9JM58, Q9XSZ1, Q9TU69, O02671, P40189, P78552

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNTF	up-regulates	CRLF1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	12
Uncertain significance	90
Likely benign	80
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322162	NM_004750.5(CRLF1):c.31_53del (p.Gln11fs)	Pathogenic
1526164	NM_004750.5(CRLF1):c.776C>A (p.Ser259Ter)	Pathogenic
1676590	NM_004750.5(CRLF1):c.713del (p.Pro238fs)	Pathogenic
1694460	NM_004750.5(CRLF1):c.771G>A (p.Trp257Ter)	Pathogenic
21008	NM_004750.5(CRLF1):c.857_864del (p.Val286fs)	Pathogenic
216913	NM_004750.5(CRLF1):c.713dup (p.Pro239fs)	Pathogenic
224612	NM_004750.5(CRLF1):c.845_846del (p.Val282fs)	Pathogenic
2425223	NC_000019.9:g.(?18709222)(18710676_?)del	Pathogenic
280836	NM_004750.5(CRLF1):c.322C>T (p.Gln108Ter)	Pathogenic
3775479	NM_004750.5(CRLF1):c.756_757del (p.Gln252fs)	Pathogenic
418665	NM_004750.5(CRLF1):c.983dup (p.Ser328fs)	Pathogenic
4736066	NM_004750.5(CRLF1):c.741_748dup (p.Glu250fs)	Pathogenic
5707	NM_004750.5(CRLF1):c.676dup (p.Thr226fs)	Pathogenic
5708	NM_004750.5(CRLF1):c.226T>G (p.Trp76Gly)	Pathogenic
5711	NM_004750.5(CRLF1):c.1102A>T (p.Lys368Ter)	Pathogenic
5712	NM_004750.5(CRLF1):c.708_709delinsT (p.Pro238fs)	Pathogenic
635333	NM_004750.5(CRLF1):c.829del (p.Arg277fs)	Pathogenic
816854	NM_004750.5(CRLF1):c.985dup (p.Glu329fs)	Pathogenic
929438	NM_004750.5(CRLF1):c.531G>A (p.Trp177Ter)	Pathogenic
1311118	NM_004750.5(CRLF1):c.616C>T (p.Pro206Ser)	Likely pathogenic
1676201	NM_004750.5(CRLF1):c.167T>C (p.Leu56Pro)	Likely pathogenic
1698520	NM_004750.5(CRLF1):c.1A>G (p.Met1Val)	Likely pathogenic
1705180	NM_004750.5(CRLF1):c.4_10del (p.Pro2fs)	Likely pathogenic
2572024	NM_004750.5(CRLF1):c.824G>C (p.Arg275Pro)	Likely pathogenic
3063901	NM_004750.5(CRLF1):c.-131_21del (p.Met1fs)	Likely pathogenic
3362563	NM_004750.5(CRLF1):c.605del (p.Ala202fs)	Likely pathogenic
3362860	NM_004750.5(CRLF1):c.828_831del (p.Arg275_Tyr276insTer)	Likely pathogenic
3583543	NM_004750.5(CRLF1):c.1213-1G>T	Likely pathogenic
3583544	NM_004750.5(CRLF1):c.855+2T>G	Likely pathogenic
4771172	NM_004750.5(CRLF1):c.226T>C (p.Trp76Arg)	Likely pathogenic

SpliceAI

2938 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18573288:T:A	acceptor_gain	1.0000
19:18573291:A:AG	acceptor_gain	1.0000
19:18573291:AGAC:A	acceptor_gain	1.0000
19:18573292:G:GG	acceptor_gain	1.0000
19:18573292:GAC:G	acceptor_gain	1.0000
19:18573292:GACG:G	acceptor_gain	1.0000
19:18573292:GACGC:G	acceptor_gain	1.0000
19:18573399:GGAGG:G	donor_gain	1.0000
19:18573400:GAGG:G	donor_gain	1.0000
19:18573400:GAGGG:G	donor_gain	1.0000
19:18573401:A:T	donor_gain	1.0000
19:18573401:AGG:A	donor_gain	1.0000
19:18573402:GG:G	donor_gain	1.0000
19:18573402:GGG:G	donor_gain	1.0000
19:18573403:GG:G	donor_gain	1.0000
19:18573404:G:GG	donor_gain	1.0000
19:18573404:GTGA:G	donor_loss	1.0000
19:18573405:T:A	donor_loss	1.0000
19:18573657:CTCA:C	acceptor_loss	1.0000
19:18573658:TCAG:T	acceptor_loss	1.0000
19:18573659:CAG:C	acceptor_loss	1.0000
19:18573660:A:AG	acceptor_gain	1.0000
19:18573660:AG:A	acceptor_gain	1.0000
19:18573661:G:GA	acceptor_gain	1.0000
19:18573661:GG:G	acceptor_gain	1.0000
19:18573661:GGT:G	acceptor_gain	1.0000
19:18573661:GGTA:G	acceptor_gain	1.0000
19:18573661:GGTAT:G	acceptor_gain	1.0000
19:18573744:GAAAG:G	donor_gain	1.0000
19:18574868:A:AG	acceptor_gain	1.0000

AlphaMissense

2698 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18596656:C:A	W330C	1.000
19:18596656:C:G	W330C	1.000
19:18596658:A:G	W330R	1.000
19:18596658:A:T	W330R	1.000
19:18596665:C:A	W327C	1.000
19:18596665:C:G	W327C	1.000
19:18596667:A:G	W327R	1.000
19:18596667:A:T	W327R	1.000
19:18596711:C:G	R312P	1.000
19:18596717:T:G	Q310P	1.000
19:18596976:C:A	W257C	1.000
19:18596976:C:G	W257C	1.000
19:18596978:A:G	W257R	1.000
19:18596978:A:T	W257R	1.000
19:18596989:A:G	L253P	1.000
19:18598834:C:A	W155C	1.000
19:18598834:C:G	W155C	1.000
19:18598836:A:G	W155R	1.000
19:18598836:A:T	W155R	1.000
19:18598841:C:G	C153S	1.000
19:18598842:A:G	C153R	1.000
19:18598842:A:T	C153S	1.000
19:18598872:A:G	C143R	1.000
19:18596653:G:C	S331R	0.999
19:18596653:G:T	S331R	0.999
19:18596655:T:G	S331R	0.999
19:18596662:A:C	S328R	0.999
19:18596662:A:T	S328R	0.999
19:18596663:C:A	S328I	0.999
19:18596664:T:G	S328R	0.999

dbSNP variants (sampled 300 via entrez): RS1000453698 (19:18606352 ACT>A), RS1000529112 (19:18603754 G>A), RS1000540279 (19:18603843 G>A,C), RS1000756769 (19:18595441 C>T), RS1001027212 (19:18598220 C>A,T), RS1001030096 (19:18601271 A>C,G), RS1001268728 (19:18598905 G>A), RS1001438262 (19:18604157 C>A), RS1001518292 (19:18606804 A>C,G), RS1001570616 (19:18606591 C>G,T), RS1001687828 (19:18595569 G>A), RS1001752026 (19:18601901 GCCTA>G), RS1001800403 (19:18593807 A>G), RS1001970580 (19:18595870 T>C), RS1002070773 (19:18606900 T>A,C,G)

Disease associations

OMIM: gene MIM:604237 | disease phenotypes: MIM:272430, MIM:601378, MIM:612657

GenCC curated gene-disease

Disease	Classification	Inheritance
Cold-induced sweating syndrome 1	Definitive	Autosomal recessive
cold-induced sweating syndrome	Supportive	Autosomal recessive
idiopathic achalasia	Supportive	Autosomal recessive

Mondo (4): Cold-induced sweating syndrome 1 (MONDO:0010091), cold-induced sweating syndrome (MONDO:0015526), cone-rod dystrophy 12 (MONDO:0012983), idiopathic achalasia (MONDO:0019635)

Orphanet (3): Crisponi syndrome (Orphanet:1545), Cold-induced sweating syndrome (Orphanet:157820), Cone rod dystrophy (Orphanet:1872)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000211	Trismus
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000293	Full cheeks
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000491	Keratitis
HP:0000670	Carious teeth
HP:0000966	Hypohidrosis
HP:0000975	Hyperhidrosis
HP:0001181	Adducted thumb
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
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:0001611	Hypernasal speech
HP:0001645	Sudden cardiac death
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0001824	Weight loss

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006585_808	Blood protein levels	1.000000e-22
GCST008295_35	Number of decayed, missing and filled tooth surfaces or use of dentures	4.000000e-08
GCST008306_17	Dentures	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010078	dentures

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567206	Cone-Rod Dystrophy 12 (supp.)
C536214	Crisponi syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
bisphenol A	affects expression, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
tobacco tar	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
ochratoxin A	increases acetylation, increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Calcitriol	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_YT49	UKMi001-A	Induced pluripotent stem cell	Female
CVCL_YT50	UKMi001-B	Induced pluripotent stem cell	Female
CVCL_YT51	UKMi001-C	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01560559	PHASE3	COMPLETED	Peroral Endoscopic Myotomy for Primary Esophageal Achalasia
NCT03784365	PHASE3	UNKNOWN	Single-Versus Multiple-dose Antimicrobial Prophylaxis for Peroral Endoscopic Myotomy in Achalasia
NCT06189859	PHASE3	RECRUITING	Electrosurgical Modes for Endoscopic Submucosal Dissection in Peroral Endoscopic Esophageal Myotomy
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02025790	Not specified	UNKNOWN	POEM Versus Pneumatic Dilatation in Achalasia Cardia
NCT03186248	Not specified	COMPLETED	Randomized Clinical Trial Comparing Short Versus Long Oesophageal Myotomy in POEM for Achalasia Cardia.
NCT03438838	Not specified	UNKNOWN	Randomised Trial Between LHM Alone Vs LHM With Anterior Fundoplication In Achalasia Cardia
NCT04951739	Not specified	COMPLETED	To Investigate the Incidence of Reflux in Patients After Per-oral Endoscopic Myotomy in Achalasia Cardia Patients
NCT05729971	Not specified	COMPLETED	Nasogastric Tube After Laparoscopic Heller-Dor Myotomy
NCT06290882	Not specified	ACTIVE_NOT_RECRUITING	Endoscopic Versus Robotic Myotomy for Treatment of Achalasia
NCT07022886	Not specified	ACTIVE_NOT_RECRUITING	INCIDENCE, PREVALENCE AND OVERALL RISK OF ESOPHAGEAL CANCER IN ACHALASIA: A PROPENSITY-MATCHED POPULATION-BASED STUDY FROM A LARGE MULTICENTER DATABASE
NCT07167355	Not specified	NOT_YET_RECRUITING	Comparison of Balloon Dilatation and Per Oral Endoscopic Myotomy in Children With Achalasia Cardia
NCT07177222	Not specified	COMPLETED	Compare the Quality of Life of Patients With Achalasia Cardia (AC) After Laparoscopic and Open Esophagocardiomyotomy.
NCT07399652	Not specified	RECRUITING	Artificial Intelligence-Guided Detection of Blood Vessels to Enhance Safety in Third-Space Endoscopic Procedures
NCT07451301	Not specified	COMPLETED	Serum Anti-enteric Neuronal Antibodies in Patients With Achalasia and Their Association With Clinical Profiles