NALCN

Chr 13

sodium leak channel, non-selective

Also known as: CLIFAHDD, CanIon, IHPRF, IHPRF1, INNFD, VGCNL1, bA430M15.1

NCBI Gene: 259232 ENSG00000102452 UniProt: Q8IZF0

The protein is a voltage-independent, nonselective cation channel that conducts persistent sodium leak current and regulates neuronal resting membrane potential and excitability as part of a channelosome complex. Mutations cause congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD) and infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves gain-of-function mutations that disrupt normal neuronal excitability.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons. This family is expressed throughout the nervous system and conducts a persistent sodium leak current that contributes to tonic neuronal excitability. The encoded protein forms a channelosome complex that includes G-protein-coupled receptors, UNC-79, UNC-80, NCA localization factor-1, and src family tyrosine kinases. Naturally occurring mutations in this gene are associated with infantile neuroaxonal dystrophy, infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) syndrome, and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD) syndrome. A knockout of the orthologous gene in mice results in paralysis with a severely disrupted respiratory rhythm, and lethality within 24 hours after birth. [provided by RefSeq, Apr 2017]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.52

Clinical Summary— NALCN

⚡

Population Constraint (gnomAD)

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 5.59

OE 0.40 (0.31–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.96Z-score

OE missense 0.56 (0.52–0.60)

563 obs / 1005.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.40 (0.31–0.52)

0≤0.351.4

Missense OE?0.56 (0.52–0.60)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 41 / 101.9Missense obs/exp: 563 / 1005.1Syn Z: 0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNALCN-related temporal lobe epilepsyOTHERAD

definitiveNALCN-related hypotonia, infantile, with psychomotor retardation and characteristic faciesLOFAR

definitiveNALCN-related congenital contractures of the limbs and face, hypotonia, and developmental delayOTHERAD

This gene — mechanism propensity

0.77top 25%

GOF

0.86top 5%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNIn vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect.1

GOFGain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability.2

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

References