CRLF1

Chr 19AR

cytokine receptor like factor 1

Also known as: CISS, CISS1, CLF, CLF-1, NR6, zcytor5

NCBI Gene: 9244 ENSG00000006016 UniProt: O75462 OMIM: 604237

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. [provided by RefSeq, Oct 2009]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.911 OMIM phenotype

Clinical Summary— CRLF1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 93 VUS of 247 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CRLF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.000

Z-score 1.86

OE 0.54 (0.33–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.91 (0.82–1.02)

224 obs / 244.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.33–0.91)

0≤0.351.4

Missense OE?0.91 (0.82–1.02)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 10 / 18.7Missense obs/exp: 224 / 244.9Syn Z: 0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCRLF1-related cold induced sweating syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7228th %ile

GOF

0.75top 25%

LOF

0.3358th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

247 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic14

VUS93

Likely Benign87

Benign23

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	2	1	0	21
Likely Pathogenic	8	6	0	0	14
VUS	2	87	3	1	93
Likely Benign	0	4	20	63	87
Benign	0	2	18	3	23
Conflicting	—				4
Total	28	101	42	67	242

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

7 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap CRLF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →