NALCN

Chr 13ADAR

sodium leak channel, non-selective

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

NCBI Gene: 259232ENSG00000102452UniProt: Q8IZF0

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]

Primary Disease Associations & Inheritance

Congenital contractures of the limbs and face, hypotonia, and developmental delayMIM #616266
AD
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1MIM #615419
AR
774
ClinVar variants
122
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NALCN
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
122 Pathogenic / Likely Pathogenic· 423 VUS of 774 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.31–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.52–0.60)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 41 / 101.9Missense obs/exp: 563 / 1005.1Syn Z: 0.13

ClinVar Variant Classifications

774 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic60
VUS423
Likely Benign182
Benign33
Conflicting14
62
Pathogenic
60
Likely Pathogenic
423
VUS
182
Likely Benign
33
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
6
45
0
62
Likely Pathogenic
18
36
6
0
60
VUS
3
370
42
8
423
Likely Benign
0
2
78
102
182
Benign
0
0
30
3
33
Conflicting
—14
Total32414201113774

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

View in ClinVar →

Protein Context — Lollipop Plot

NALCN · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NALCN-related temporal lobe epilepsy

limited
ADUndetermined Non-Loss-Of-FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

NALCN-related hypotonia, infantile, with psychomotor retardation and characteristic facies

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

NALCN-related congenital contractures of the limbs and face, hypotonia, and developmental delay

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Congenital contractures of the limbs and face, hypotonia, and developmental delay

MIM #616266

Molecular basis of disorder known

Autosomal dominant

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

MIM #615419

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NALCN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genotype-Phenotype Landscape of NALCN and UNC80-Related Disorders.
Parra-Díaz P et al.·Neurology
2025
A new neurodevelopmental disorder linked to heterozygous variants in UNC79.
Bayat A et al.·Genet Med
2023
Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants.
Sartorelli J et al.·Neuropediatrics
2025Review
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Biankin AV et al.·Nature
2012
Severe central sleep apnea in a child with biallelic variants in NALCN.
Maselli K et al.·J Clin Sleep Med
2022Review
Novel NALCN variant linked to temporal lobe epilepsy.
Nguyen E et al.·Am J Med Genet A
2023Case report
Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.
Buers I et al.·Clin Genet
2020Review
A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.
Ope O et al.·Am J Med Genet A
2020Case report
A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment.
Cabrita Pinto RL et al.·Genes (Basel)
2025Case report
Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection.
Tehrani Fateh S et al.·Neurol Sci
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools