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.

GeneReviews OMIM 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital contractures of the limbs and face, hypotonia, and developmental delayMIM #616266

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1MIM #615419

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Congenital contractures of the limbs and face, hypotonia, and developmental delay; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — NALCN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in NALCN?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

1,566 rare PASS variants

Rare truncating (LoF)

1 in 490

256 rare PASS variants

Rare synonymous (reference)

1 in 63

845 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NALCN. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 59	1 in 600
South Asian	~43k	1 in 52	1 in 470
Remaining (unassigned)	~30k	1 in 44	1 in 510
European (Finnish)	~27k	1 in 100	1 in 1,500
Admixed American	~22k	1 in 51	1 in 1,100
African / African American	~21k	1 in 53	1 in 900
East Asian	~20k	1 in 52	1 in 510
Ashkenazi Jewish	~13k	1 in 270	1 in 970
Middle Eastern	~2,884	1 in 45	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 35 of 43 coding exons well covered in gnomAD exomes; exons 4, 12, 13, 27, 28 and 3 more marginal. Genomes: all 43.? see exons ↓