NALCN

Chr 13ADAR

sodium leak channel, non-selective

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

NCBI Gene: 259232 ENSG00000102452 UniProt: Q8IZF0 OMIM: 611549

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismAD/ARLOEUF 0.522 OMIM phenotypes

Clinical Summary— NALCN

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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

100 unique Pathogenic / Likely Pathogenic· 130 VUS of 386 total submissions

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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 OE0.40 (0.31–0.52)

0≤0.351.4

Missense OE0.56 (0.52–0.60)

0≤0.61.4

Synonymous OE0.99

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

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.PMID:25683120

GOFGain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability.PMID:31601786

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