CNTFR

Chr 9

ciliary neurotrophic factor receptor

ENSG00000122756 UniProt: P26992 OMIM: 118946

The ciliary neurotrophic factor receptor (CNTFR) encodes the ligand-specific alpha subunit of a tripartite cytokine receptor that binds ciliary neurotrophic factor and mediates neuronal survival, differentiation, and gene expression. This gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.34) and mutations cause ciliary neurotrophic factor receptor deficiency, an autosomal recessive disorder affecting the nervous system. The condition involves impaired neuronal signaling pathways critical for motor neuron survival and muscle function.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.34

Clinical Summary— CNTFR

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.34LOEUF

pLI 0.955

Z-score 3.56

OE 0.11 (0.04–0.34)

Highly constrained

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

Missense Constraint

1.60Z-score

OE missense 0.71 (0.62–0.80)

166 obs / 235.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.11 (0.04–0.34)

0≤0.351.4

Missense OE0.71 (0.62–0.80)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 2 / 18.6Missense obs/exp: 166 / 235.0Syn Z: 0.44

0.4884th %ile

GOF

0.6833th %ile

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.34

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.