NALCN

Summary

NALCN (sodium leak channel, non-selective, HGNC:19082) is a protein-coding gene on chromosome 13q32.3-q33.1, encoding Sodium leak channel NALCN (Q8IZF0). Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.

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.

Source: NCBI Gene 259232 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 1,341 total — 79 pathogenic, 81 likely-pathogenic
• Phenotypes (HPO): 123
• MANE Select transcript: NM_052867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19082
Approved symbol	NALCN
Name	sodium leak channel, non-selective
Location	13q32.3-q33.1
Locus type	gene with protein product
Status	Approved
Aliases	bA430M15.1, CanIon
Ensembl gene	ENSG00000102452
Ensembl biotype	protein_coding
OMIM	611549
Entrez	259232

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 7 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000251127, ENST00000376200, ENST00000467264, ENST00000470333, ENST00000497170, ENST00000648359, ENST00000674840, ENST00000674904, ENST00000675075, ENST00000675150, ENST00000675332, ENST00000675415, ENST00000675594, ENST00000675802, ENST00000675891, ENST00000676315, ENST00000676357, ENST00000676439, ENST00000858715, ENST00000949518, ENST00000949519

RefSeq mRNA: 5 — MANE Select: NM_052867 NM_001350748, NM_001350749, NM_001350750, NM_001350751, NM_052867

CCDS: CCDS91831, CCDS91832, CCDS9498

Canonical transcript exons

ENST00000251127 — 44 exons

Exon	Start	End
ENSE00000685849	101104295	101104426
ENSE00000685852	101104530	101104650
ENSE00000685855	101107487	101107609
ENSE00000685856	101107698	101107789
ENSE00000685858	101110619	101110688
ENSE00000685860	101111125	101111226
ENSE00000854009	101100784	101100888
ENSE00000854010	101103172	101103339
ENSE00000917052	101057939	101058056
ENSE00000917053	101059818	101059967
ENSE00000917054	101061968	101062118
ENSE00000917055	101065404	101065561
ENSE00000917056	101068695	101068827
ENSE00000917057	101073584	101073677
ENSE00000917058	101074514	101074662
ENSE00000940225	101089846	101089966
ENSE00000940226	101089663	101089761
ENSE00000940227	101083711	101083804
ENSE00000940228	101082809	101082883
ENSE00000940229	101081527	101081646
ENSE00000998709	101067918	101068033
ENSE00000998711	101095574	101095680
ENSE00000998713	101104894	101104950
ENSE00000998714	101083092	101083198
ENSE00001151912	101053776	101055488
ENSE00001228983	101075873	101075941
ENSE00001614390	101416313	101416508
ENSE00003500079	101376917	101377056
ENSE00003508516	101258443	101258574
ENSE00003538255	101395183	101395365
ENSE00003585561	101229393	101229584
ENSE00003587873	101124608	101124681
ENSE00003623152	101283933	101284019
ENSE00003624284	101399019	101399165
ENSE00003626631	101176300	101176374
ENSE00003630239	101144760	101144896
ENSE00003632562	101292224	101292366
ENSE00003634519	101376700	101376828
ENSE00003637459	101191917	101192054
ENSE00003643107	101291990	101292094
ENSE00003644739	101345266	101345420
ENSE00003671873	101237755	101237922
ENSE00003675791	101378570	101378653
ENSE00003686733	101143080	101143221

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 95.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4606 / max 101.9645, expressed in 1046 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138067	3.9495	1033
138062	0.1642	75
138065	0.1463	74
138064	0.0843	51
138066	0.0745	39
138063	0.0418	25

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	95.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.23	gold quality
corpus callosum	UBERON:0002336	94.92	gold quality
endothelial cell	CL:0000115	94.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.11	gold quality
postcentral gyrus	UBERON:0002581	94.02	gold quality
entorhinal cortex	UBERON:0002728	93.84	gold quality
parietal lobe	UBERON:0001872	93.66	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.20	gold quality
superior frontal gyrus	UBERON:0002661	92.94	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.09	gold quality
pigmented layer of retina	UBERON:0001782	91.74	gold quality
subthalamic nucleus	UBERON:0001906	91.43	gold quality
substantia nigra pars compacta	UBERON:0001965	91.42	gold quality
lateral globus pallidus	UBERON:0002476	91.04	gold quality
medulla oblongata	UBERON:0001896	90.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.98	gold quality
cerebellar vermis	UBERON:0004720	90.61	gold quality
inferior vagus X ganglion	UBERON:0005363	90.57	gold quality
occipital lobe	UBERON:0002021	90.52	gold quality
primary visual cortex	UBERON:0002436	90.08	gold quality
superior vestibular nucleus	UBERON:0007227	89.96	gold quality
pons	UBERON:0000988	88.42	gold quality
ventral tegmental area	UBERON:0002691	87.83	gold quality
prefrontal cortex	UBERON:0000451	87.82	gold quality
globus pallidus	UBERON:0001875	87.69	gold quality
temporal lobe	UBERON:0001871	87.64	gold quality
Ammon’s horn	UBERON:0001954	87.61	gold quality
frontal cortex	UBERON:0001870	87.54	gold quality
frontal lobe	UBERON:0016525	87.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	12.63
E-ANND-3	yes	7.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

87 targeting NALCN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6885-3P	99.75	70.36	3187

Literature-anchored findings (GeneRIF, showing 27)

• UNC80 functions as a scaffold for Src kinases in NALCN channel function. (PMID:19535918)
• Data show the molecular basis of a muscarinic-activated inward sodium current that is independent of G-protein activation, and provide new insights into the properties of NALCN channels. (PMID:19575010)
• This study observed nominal association with rs9518320 and rs9518331, suggesting that NALCN is not related to schizophrenia risk. (PMID:20674038)
• NALCN is the gene responsible for INAD with facial dysmorphism (PMID:23749988)
• Two mutations, one missense and one nonsense, in NALCN in two unrelated families. (PMID:24075186)
• This study found a plausible association, though not statistically confirmed, of cervical dystonia with SNPs in the NALCN region. (PMID:24227479)
• We used exome and targeted next-generation sequencing to identify de novo mutations in NALCN as the cause of a newly delineated condition, CLIFAHDD syndrome. (PMID:25683120)
• Ohmic leak currents were identified in freshly isolated and cultured myometrial smooth muscle cells. NALCN contributes to this current. Uterine biopsies from term, non-laboring women revealed NALCN messenger RNA and protein expression in the myometrium. (PMID:26134120)
• UNC80 bridges between UNC79 and the cation channel NALCN. (PMID:26545877)
• UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex (PMID:26708753)
• The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment. (PMID:26763878)
• Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice. (PMID:26923739)
• Two patients with novel mutations (p.F317C and p.V595F) and distal arthrogryposis and central hypertonicity are described. (PMID:27214504)
• Study identified a de novo missense mutation in NALCN, c.1768C>T, in an infant with a severe neonatal lethal form of the recently characterized congenital contractures of the limbs and face with hypotonia and developmental delay. Clinical phenotype and electrophysiologic studies show sustained muscular contraction in response to transient sensory stimuli. (PMID:27558372)
• 4 patients with intellectual disability, small cerebellum, and contractures with novel, de novo predicted deleterious missense variants in NALCN are reported. (PMID:28133733)
• these are the first European cases with Infantile hypotonia with psychomotor retardation and characteristic facies-1 syndrome with biallelic truncating mutations of NALCN. (PMID:29399786)
• 9-year-old male with a homozygous nonsense mutation in NALCN (c.3910C>T, p.Arg1304X) leading to profound intellectual disability, seizures, feeding difficulties, and significant periodic breathing. (PMID:29968795)
• NALCN variant is associated with neurodevelopmental diseases. (PMID:30167850)
• Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. (PMID:31409833)
• PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases (PMID:31601786)
• A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly. (PMID:32618095)
• Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. (PMID:32620897)
• Structure of the human sodium leak channel NALCN. (PMID:32698188)
• Structure of the human sodium leak channel NALCN in complex with FAM155A. (PMID:33203861)
• Structural architecture of the human NALCN channelosome. (PMID:34929720)
• Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection. (PMID:37452996)
• New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN. (PMID:37615954)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nalcn	ENSDARG00000001835
mus_musculus	Nalcn	ENSMUSG00000000197
rattus_norvegicus	Nalcn	ENSRNOG00000004752
drosophila_melanogaster	na	FBGN0002917
caenorhabditis_elegans		WBGENE00003558
caenorhabditis_elegans		WBGENE00008911

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), SCN3A (ENSG00000153253), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Sodium leak channel NALCN — Q8IZF0 (reviewed: Q8IZF0)

Alternative names: CanIon, Sodium leak channel non-selective protein, Voltage gated channel-like protein 1

All UniProt accessions (9): Q8IZF0, A0A3B3ISV8, A0A6Q8PF19, A0A6Q8PFJ2, A0A6Q8PFS9, A0A6Q8PG91, A0A6Q8PGX7, A0A6Q8PHC5, A0A6Q8PHH0

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability. NALCN channel functions as a multi-protein complex, which consists at least of NALCN, NALF1, UNC79 and UNC80. NALCN is the voltage-sensing, pore-forming subunit of the NALCN channel complex. NALCN channel complex is constitutively active and conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations. In addition to its role in regulating neuronal excitability, is required for normal respiratory rhythm, systemic osmoregulation by controlling the serum sodium concentration and in the regulation of the intestinal pace-making activity in the interstitial cells of Cajal. NALCN channel is also activated by neuropeptides such as neurotensin and substance P (SP) through a SRC family kinases-dependent pathway. In addition, NALCN activity is enhanced/modulated by several GPCRs, such as CHRM3.

Subunit / interactions. Found in a complex with NALCN, UNC79, UNC80 and NACL1; these auxiliary subunits are indispensable for the function of NALCN channel. Interacts with UNC80; required for the NALCN activation/inhibition by GPCRs in neurons. Found in a complex with NALCN, UNC79 and UNC80; UNC80 bridges NALCN to UNC79. Interacts with CHRM3.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylated on tyrosine residues.

Disease relevance. Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (IHPRF1) [MIM:615419] A neurodegenerative disease characterized by variable degrees of hypotonia, speech impairment, intellectual disability, pyramidal signs, subtle facial dysmorphism, and chronic constipation. Some patients manifest neuroaxonal dystrophy, optic atrophy, unmyelinated axons and spheroid bodies in tissue biopsies. The disease is caused by variants affecting the gene represented in this entry. Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) [MIM:616266] A disease characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, abnormal tone, most commonly manifested as hypotonia, and variable degrees of developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by low micromolar concentrations of Gd(3+) and high micromolar concentrations of verapamil. Insensitive to tetrodotoxin (TTX) and potentiated by low external Ca(2+) concentration.

Domain organisation. Contains 24 transmembrane helices (TM) that form four homologous functional repeats connected by intracellular linkers. Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments represent the voltage-sensor. S4 transmembrane segments lack some of the charged residues (K and R) found at every third position in the S4s of the NaV, CaV, and KV channels. Pore-forming loops (P loops) between S5 and S6 of each domain form an EEKE sodium- ion selectivity filter a mixture between the EEEE found in the CaVs and the DEKA of NaVs. Voltage-sensing domains (VSDs), formed by S1 to S4 of each domain, detect changes in membrane potential and induce the opening or closing of the ion-conducting pore domain, formed by S5 and S6.

Similarity. Belongs to the NALCN family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IZF0-1	1	yes
Q8IZF0-2	2
Q8IZF0-3	3

RefSeq proteins (5): NP_001337677, NP_001337678, NP_001337679, NP_001337680, NP_443099* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005821	Ion_trans_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028823	NALCN	Family

Pfam: PF00520

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (226 total): helix 76, topological domain 29, strand 26, transmembrane region 24, mutagenesis site 23, sequence variant 14, turn 13, intramembrane region 4, disulfide bond 4, splice variant 4, glycosylation site 3, region of interest 2, compositionally biased region 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6XIW	ELECTRON MICROSCOPY	2.8
7CM3	ELECTRON MICROSCOPY	3.1
7SX3	ELECTRON MICROSCOPY	3.1
7SX4	ELECTRON MICROSCOPY	3.5
7WJI	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZF0-F1	77.05	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 207–239, 229–245, 1046–1057, 1405–1417

Glycosylation sites (3): 210, 216, 1064

Mutagenesis-validated functional residues (23):

Position	Phenotype
554	drastically more sensitive to ca(2+) block.
558	moderately more sensitive to ca(2+) block.
561	no effect on the blockage of nalcn pore by ca(2+).
989	does not affect the voltage sensitivity.
992	does not affect the voltage sensitivity.
995	does not affect the voltage sensitivity.
1115	no effect on the blockage of nalcn pore by ca(2+).
1119	moderately more sensitive to ca(2+) block.
1310	does not affect the voltage sensitivity.
1389	moderately more sensitive to ca(2+) block.
1390	drastically more sensitive to ca(2+) block.
146	affects voltage sensitivity.
152	affects voltage sensitivity.
155	affects voltage sensitivity.
280	drastically more sensitive to ca(2+) block.
325	increases channel activity.
328	increases channel activity.
332	no effect on the channel activity.
481	exhibits altered current kinetics.
484	does not exhibited altered current kinetics.
487	does not exhibited altered current kinetics.
504	decreases channel activity.
505	decreases channel activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 349 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_SYNAPTIC_TRANSMISSION_CHOLINERGIC, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, RYTAAWNNNTGAY_UNKNOWN, GOBP_REGULATION_OF_ACTION_POTENTIAL, GOBP_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_SYNAPTIC_SIGNALING, GOBP_REGULATION_OF_SYSTEM_PROCESS, ABBUD_LIF_SIGNALING_2_DN, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GABAERGIC

GO Biological Process (11): positive regulation of synaptic transmission, cholinergic (GO:0032224), positive regulation of synaptic transmission, GABAergic (GO:0032230), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), regulation of resting membrane potential (GO:0060075), calcium ion transmembrane transport (GO:0070588), potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), transmembrane transport (GO:0055085), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (6): voltage-gated sodium channel activity (GO:0005248), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272), leak channel activity (GO:0022840), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), monoatomic ion channel complex (GO:0034702), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation transmembrane transport	3
positive regulation of synaptic transmission	2
transport	2
synaptic transmission, cholinergic	1
regulation of synaptic transmission, cholinergic	1
regulation of synaptic transmission, GABAergic	1
synaptic transmission, GABAergic	1
monoatomic ion transport	1
transmembrane transport	1
sodium ion transport	1
regulation of membrane potential	1
calcium ion transport	1
potassium ion transport	1
metal ion transport	1
cellular process	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
sodium channel activity	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
monoatomic cation channel activity	1
sodium ion transmembrane transporter activity	1
narrow pore channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
binding	1
membrane	1
cell periphery	1
transmembrane transporter complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NALCN	UNC80	Q8N2C7	996
NALCN	UNC79	Q9P2D8	962
NALCN	TACR1	P25103	874
NALCN	NTS	P30990	843
NALCN	TAC1	P20366	822
NALCN	NALF1	B1AL88	761
NALCN	C2CD4A	Q8NCU7	715
NALCN	OR4B1	Q8NGF8	571
NALCN	OR4X2	Q8NGF9	545
NALCN	CEACAM4	O75871	542
NALCN	SIK3	Q9Y2K2	533
NALCN	NAV1	Q8NEY1	500
NALCN	NALF2	O75949	494
NALCN	HCN3	Q9P1Z3	458
NALCN	CLCN3	P51790	452

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CALM1	NALF1	psi-mi:“MI:0915”(physical association)	0.570
NALCN	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	NALCN	psi-mi:“MI:0915”(physical association)	0.560
NALCN	CHRM3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): NALCN (Two-hybrid), NALCN (Proximity Label-MS), PSMD11 (Affinity Capture-MS), NALCN (Two-hybrid), NALCN (Affinity Capture-MS), STX8 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0JMD4, B7ZC96, F6RG56, O65718, O73606, P17971, P17972, P70259, P97557, Q00195, Q03041, Q05973, Q0P583, Q16280, Q16281, Q24278, Q28718, Q29441, Q3U2S8, Q3UW12, Q5F4C0, Q5R5V8, Q5RC10, Q60565, Q62398, Q64359, Q6PIU1, Q6Q760, Q6R6I7, Q8AYS8, Q8BWC0, Q8BXR5, Q8BZN2, Q8IV77, Q8IZF0, Q8IZK6, Q8K595, Q8TDD5, Q90980, Q94AS9

Diamond homologs: A2APX8, A2ASI5, B1AWN6, C9D7C2, J9VTB0, O00555, O08562, O35505, O42398, O43497, O54898, O55017, O57483, O60840, O73700, O73705, O73706, O73707, O88420, O88427, O88457, O95180, P02719, P04774, P04775, P07293, P08104, P15381, P15389, P15390, P22002, P22316, P27732, P27884, P35498, P35499, P35500, P54282, P56698, P56699

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
UNC80	“up-regulates activity”	NALCN	binding
NALCN	“up-regulates quantity”	sodium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

1341 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	79
Likely pathogenic	81
Uncertain significance	542
Likely benign	394
Benign	143

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172692	NM_052867.4(NALCN):c.4194_4197del (p.Cys1398fs)	Pathogenic
1180618	NM_052867.4(NALCN):c.1313G>A (p.Trp438Ter)	Pathogenic
1201677	NM_052867.4(NALCN):c.2524C>T (p.Arg842Ter)	Pathogenic
1254313	NM_052867.4(NALCN):c.303del (p.Tyr102fs)	Pathogenic
1321952	NM_052867.4(NALCN):c.4654G>A (p.Glu1552Lys)	Pathogenic
1687235	NM_052867.4(NALCN):c.454C>T (p.Arg152Ter)	Pathogenic
1698711	NM_052867.4(NALCN):c.1789G>A (p.Val597Ile)	Pathogenic
1705481	NM_052867.4(NALCN):c.4447-2del	Pathogenic
187771	NM_052867.4(NALCN):c.530A>C (p.Gln177Pro)	Pathogenic
187772	NM_052867.4(NALCN):c.938T>G (p.Val313Gly)	Pathogenic
187773	NM_052867.4(NALCN):c.1768C>T (p.Leu590Phe)	Pathogenic
187774	NM_052867.4(NALCN):c.1526T>C (p.Leu509Ser)	Pathogenic
187775	NM_052867.4(NALCN):c.1733A>C (p.Tyr578Ser)	Pathogenic
2000783	NM_052867.4(NALCN):c.1314G>A (p.Trp438Ter)	Pathogenic
2018443	NM_052867.4(NALCN):c.609del (p.Phe203fs)	Pathogenic
222073	NM_052867.4(NALCN):c.3390G>A (p.Pro1130=)	Pathogenic
225072	NM_052867.4(NALCN):c.4197+1G>A	Pathogenic
225108	NM_052867.4(NALCN):c.2203C>T (p.Arg735Ter)	Pathogenic
235830	NM_052867.4(NALCN):c.4338T>G (p.Ile1446Met)	Pathogenic
235832	NM_052867.4(NALCN):c.3050T>C (p.Ile1017Thr)	Pathogenic
235833	NM_052867.4(NALCN):c.3017T>C (p.Val1006Ala)	Pathogenic
235834	NM_052867.4(NALCN):c.1538C>A (p.Thr513Asn)	Pathogenic
235835	NM_052867.4(NALCN):c.1534T>G (p.Phe512Val)	Pathogenic
235836	NM_052867.4(NALCN):c.979G>A (p.Glu327Lys)	Pathogenic
235837	NM_052867.4(NALCN):c.934C>A (p.Leu312Ile)	Pathogenic
2427152	NC_000013.10:g.(?101936264)(101944737_?)del	Pathogenic
2443941	NM_052867.4(NALCN):c.2022_2023del (p.Cys675fs)	Pathogenic
2576683	NM_052867.4(NALCN):c.1745A>G (p.Tyr582Cys)	Pathogenic
2578708	NM_052867.4(NALCN):c.2831del (p.Phe944fs)	Pathogenic
2662979	NM_052867.4(NALCN):c.3058G>T (p.Val1020Phe)	Pathogenic

SpliceAI

8353 predictions. Top by Δscore:

Variant	Effect	Δscore
13:101057934:CCTA:C	donor_loss	1.0000
13:101058052:CTTGT:C	acceptor_gain	1.0000
13:101058053:TTGT:T	acceptor_gain	1.0000
13:101058054:TGT:T	acceptor_gain	1.0000
13:101058054:TGTCT:T	acceptor_loss	1.0000
13:101058055:GT:G	acceptor_gain	1.0000
13:101058056:TC:T	acceptor_loss	1.0000
13:101058057:C:CC	acceptor_gain	1.0000
13:101058058:T:A	acceptor_loss	1.0000
13:101058060:C:CT	acceptor_gain	1.0000
13:101058061:A:AC	acceptor_gain	1.0000
13:101058061:A:C	acceptor_gain	1.0000
13:101059813:CATA:C	donor_loss	1.0000
13:101059815:TAC:T	donor_loss	1.0000
13:101059816:A:AT	donor_loss	1.0000
13:101059817:C:G	donor_loss	1.0000
13:101059968:C:CC	acceptor_gain	1.0000
13:101061962:ACTC:A	donor_loss	1.0000
13:101061963:CTCA:C	donor_loss	1.0000
13:101061964:TCAC:T	donor_loss	1.0000
13:101061966:A:AC	donor_gain	1.0000
13:101061966:ACAG:A	donor_gain	1.0000
13:101061966:ACAGC:A	donor_loss	1.0000
13:101061967:C:CA	donor_gain	1.0000
13:101061967:CA:C	donor_gain	1.0000
13:101061967:CAG:C	donor_gain	1.0000
13:101061967:CAGC:C	donor_gain	1.0000
13:101061967:CAGCT:C	donor_gain	1.0000
13:101061991:T:TA	donor_gain	1.0000
13:101062114:GCATG:G	acceptor_gain	1.0000

AlphaMissense

11546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:101061996:A:G	L1576P	1.000
13:101061998:C:A	W1575C	1.000
13:101061998:C:G	W1575C	1.000
13:101062000:A:G	W1575R	1.000
13:101062000:A:T	W1575R	1.000
13:101062005:C:G	R1573P	1.000
13:101062008:A:C	I1572S	1.000
13:101062008:A:G	I1572T	1.000
13:101062008:A:T	I1572N	1.000
13:101062020:G:T	A1568D	1.000
13:101062021:C:G	A1568P	1.000
13:101062035:A:T	I1563K	1.000
13:101062047:A:G	L1559P	1.000
13:101062065:A:G	L1553P	1.000
13:101065418:G:C	F1530L	1.000
13:101065418:G:T	F1530L	1.000
13:101065420:A:G	F1530L	1.000
13:101067942:C:A	W1474C	1.000
13:101067942:C:G	W1474C	1.000
13:101067943:C:G	W1474S	1.000
13:101067944:A:G	W1474R	1.000
13:101067944:A:T	W1474R	1.000
13:101067964:A:G	L1467P	1.000
13:101068014:G:C	F1450L	1.000
13:101068014:G:T	F1450L	1.000
13:101068016:A:G	F1450L	1.000
13:101068703:A:G	L1441P	1.000
13:101068810:A:C	C1405W	1.000
13:101068811:C:G	C1405S	1.000
13:101068811:C:T	C1405Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000002805 (13:101054727 T>C), RS1000008843 (13:101152660 G>A,T), RS1000013416 (13:101275268 C>T), RS1000024215 (13:101078760 G>T), RS1000025633 (13:101200518 C>T), RS1000027551 (13:101278819 A>G), RS1000045019 (13:101232234 A>T), RS1000048920 (13:101158707 G>C), RS1000052942 (13:101168321 A>G), RS1000058063 (13:101200682 T>C), RS1000068378 (13:101286773 G>T), RS1000081894 (13:101152199 A>G), RS1000082354 (13:101248427 T>C), RS1000089316 (13:101115057 T>C), RS1000092891 (13:101241499 C>T)

Disease associations

OMIM: gene MIM:611549 | disease phenotypes: MIM:616266, MIM:615419, MIM:192350, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotonia, infantile, with psychomotor retardation and characteristic facies 1	Definitive	Autosomal recessive
congenital contractures of the limbs and face, hypotonia, and developmental delay	Definitive	Autosomal dominant
hypotonia, infantile, with psychomotor retardation and characteristic facies	Strong	Autosomal recessive
digitotalar dysmorphism	Supportive	Autosomal dominant
Sheldon-hall syndrome	Supportive	Autosomal dominant
Freeman-Sheldon syndrome	Supportive	Autosomal dominant
temporal lobe epilepsy	Limited	Autosomal dominant

Mondo (16): congenital contractures of the limbs and face, hypotonia, and developmental delay (MONDO:0014556), hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MONDO:0024567), intellectual disability (MONDO:0001071), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder (MONDO:0700092), hypotonia, infantile, with psychomotor retardation and characteristic facies (MONDO:0014176), strabismus (MONDO:0003432), autism spectrum disorder (MONDO:0005258), arthrogryposis syndrome (MONDO:0015225), VACTERL/vater association (MONDO:0008642), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), digitotalar dysmorphism (MONDO:0015240), Sheldon-hall syndrome (MONDO:0011128), Freeman-Sheldon syndrome (MONDO:0008675)

Orphanet (9): Congenital limbs-face contractures-hypotonia-developmental delay syndrome (Orphanet:562528), Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet:371364), Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency (Orphanet:700336), Arthrogryposis syndrome (Orphanet:109007), VACTERL/VATER association (Orphanet:887), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

123 total (30 of 123 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000205	Pursed lips
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000417	Slender nose
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000457	Depressed nasal ridge

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000821_18	Bipolar disorder and schizophrenia	5.000000e-07
GCST001542_2	HIV-associated dementia	7.000000e-07
GCST001734_12	Non-small cell lung cancer	9.000000e-06
GCST002211_8	Psychosis (atypical)	3.000000e-06
GCST003135_9	Bipolar disorder and eating disorder	6.000000e-06
GCST003542_50	Night sleep phenotypes	7.000000e-06
GCST004639_35	Prudent dietary pattern	7.000000e-06
GCST004751_5	Serum uric acid levels in response to allopurinol in gout	5.000000e-07
GCST005230_1	Recurrent major depressive disorder	6.000000e-06
GCST009440_10	Age-related cognitive decline (attention/processing speed) (slope of z-scores)	4.000000e-06
GCST009440_11	Age-related cognitive decline (attention/processing speed) (slope of z-scores)	3.000000e-06
GCST010002_194	Refractive error	2.000000e-76
GCST012046_6	Fasting insulin	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004761	uric acid measurement
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D004833	Epilepsy, Temporal Lobe	C10.228.140.490.360.290; C10.228.140.490.493.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D013285	Strabismus	C10.292.562.887; C11.590.810
C565097	Digitotalar Dysmorphism (supp.)
C535483	Freeman-Sheldon syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7992226	Other	3	methotrexate	Acute lymphoblastic leukemia

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7992226	NALCN	3	0.00	1	methotrexate
rs9585618	NALCN		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Sodium leak channel, non-selective (NALCN)

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
Gd3+	Channel blocker	5.6	pIC50
Ca2+	Channel blocker	3.88	pIC50
Cd2+	Channel blocker	3.8	pIC50
Co2+	Channel blocker	3.6	pIC50
verapamil	Channel blocker	3.4	pIC50

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance	2
Nickel	decreases expression	2
Valproic Acid	affects cotreatment, increases expression, decreases methylation	2
propionaldehyde	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
aflatoxin B2	increases methylation	1
cyanoginosin LR	decreases expression, increases methylation	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Progesterone	increases expression	1
Aflatoxin B1	decreases methylation	1
Palmitic Acid	increases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F0YI	GM29787	Induced pluripotent stem cell	Female
CVCL_F0YJ	GM29788	Finite cell line	Female

Clinical trials (associated diseases)

321 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00595699	PHASE4	COMPLETED	Escitalopram Treatment of Major Depression in Patients With Temporal Lobe Epilepsy
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00717431	PHASE3	TERMINATED	A Multicenter Study of Hippocampal Electrical Stimulation (HS, in Mesial Temporal Lobe Epilepsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05179083	PHASE1	UNKNOWN	Exercise for Brain Regeneration in Epilepsy
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05419245	Not specified	UNKNOWN	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT00344877	Not specified	COMPLETED	Electrical Brain Stimulation to Reduce Epileptic Seizures
NCT02590419	Not specified	UNKNOWN	Application of Diffusion Tensor Imaging and Tractography in Epilepsy Surgery
NCT02844465	Not specified	COMPLETED	Stereotactic Laser Ablation for Temporal Lobe Epilepsy (Slate)
NCT02946151	Not specified	COMPLETED	Subcutaneous EEG in Epilepsy
NCT03643471	Not specified	UNKNOWN	Advanced Magnetic Resonance Imaging in Temporal Lobe Epilepsy
NCT04055532	Not specified	WITHDRAWN	Biomarkers in Neurodegenerative Diseases
NCT05019404	Not specified	UNKNOWN	Minimally Invasive Surgical Epilepsy Trial for Temporal Lobe Epilepsy
NCT05159609	Not specified	COMPLETED	Closed Loop Auditory Stimulus in Sleep and epilepsY
NCT05609084	Not specified	RECRUITING	Intensive Preoperative Speech Rehabilitation in Drug-Resistant Temporal Epilepsy