NALF1

Summary

NALF1 (NALCN channel auxiliary factor 1, HGNC:33877) is a protein-coding gene on chromosome 13q33.3, encoding NALCN channel auxiliary factor 1 (B1AL88). Auxillary component of the NALCN sodium channel complex, a channel that regulates the resting membrane potential and controls neuronal excitability.

Predicted to contribute to stretch-activated, monoatomic cation-selective, calcium channel activity. Predicted to be involved in calcium ion import across plasma membrane. Located in plasma membrane.

Source: NCBI Gene 728215 — RefSeq curated summary.

At a glance

• GWAS associations: 44
• Clinical variants (ClinVar): 72 total — 3 pathogenic
• MANE Select transcript: NM_001080396

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33877
Approved symbol	NALF1
Name	NALCN channel auxiliary factor 1
Location	13q33.3
Locus type	gene with protein product
Status	Approved
Aliases	NLF-1
Ensembl gene	ENSG00000204442
Ensembl biotype	protein_coding
OMIM	619899
Entrez	728215

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000375915

RefSeq mRNA: 1 — MANE Select: NM_001080396 NM_001080396

CCDS: CCDS32006

Canonical transcript exons

ENST00000375915 — 3 exons

Exon	Start	End
ENSE00001468794	107163510	107170786
ENSE00001468797	107210584	107210755
ENSE00001468799	107865682	107867496

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 95.36.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0488 / max 68.7957, expressed in 688 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138168	1.2515	553
138167	0.4012	178
138166	0.2821	146
138165	0.1140	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	95.36	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.31	gold quality
buccal mucosa cell	CL:0002336	95.17	gold quality
middle temporal gyrus	UBERON:0002771	89.76	gold quality
amniotic fluid	UBERON:0000173	88.59	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.33	gold quality
primary visual cortex	UBERON:0002436	88.10	gold quality
postcentral gyrus	UBERON:0002581	86.99	gold quality
entorhinal cortex	UBERON:0002728	86.96	gold quality
superior frontal gyrus	UBERON:0002661	86.24	gold quality
parietal lobe	UBERON:0001872	86.05	gold quality
occipital lobe	UBERON:0002021	85.70	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.28	gold quality
cerebellar vermis	UBERON:0004720	82.76	gold quality
frontal pole	UBERON:0002795	81.39	gold quality
CA1 field of hippocampus	UBERON:0003881	81.28	gold quality
cortical plate	UBERON:0005343	81.20	gold quality
substantia nigra pars compacta	UBERON:0001965	80.24	gold quality
stromal cell of endometrium	CL:0002255	80.11	gold quality
prefrontal cortex	UBERON:0000451	80.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.76	gold quality
cerebral cortex	UBERON:0000956	79.69	gold quality
frontal cortex	UBERON:0001870	79.39	gold quality
neocortex	UBERON:0001950	79.13	gold quality
temporal lobe	UBERON:0001871	79.01	gold quality
Brodmann (1909) area 10	UBERON:0013541	78.70	gold quality
Ammon’s horn	UBERON:0001954	78.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.73	gold quality
endometrium epithelium	UBERON:0004811	77.69	gold quality
superior vestibular nucleus	UBERON:0007227	76.97	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	4764.45
E-HCAD-35	yes	87.98
E-HCAD-25	yes	76.21
E-HCAD-5	yes	17.11
E-HCAD-30	no	2961.17
E-ANND-3	no	4.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

181 targeting NALF1, 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-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-495-3P	99.96	72.81	4197

Literature-anchored findings (GeneRIF, showing 5)

• FAM155A rs67153654-A association with diverticulitis in Iceland and Denmark population. (PMID:28585551)
• Low FAM155A expression is associated with glioma. (PMID:29885519)
• Common variation in FAM155A is associated with diverticulitis but not diverticulosis. (PMID:32015353)
• Structure of the human sodium leak channel NALCN. (PMID:32698188)
• Structure of the human sodium leak channel NALCN in complex with FAM155A. (PMID:33203861)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nalf1a	ENSDARG00000075858
mus_musculus	Nalf1	ENSMUSG00000079157
rattus_norvegicus	Nalf1	ENSRNOG00000066120
drosophila_melanogaster	Mid1	FBGN0053988

Paralogs (1): NALF2 (ENSG00000130054)

Protein

Protein identifiers

NALCN channel auxiliary factor 1 — B1AL88 (reviewed: B1AL88)

Alternative names: Transmembrane protein FAM155A

All UniProt accessions (1): B1AL88

UniProt curated annotations — full annotation on UniProt →

Function. Auxillary component of the NALCN sodium channel complex, a channel that regulates the resting membrane potential and controls neuronal excitability.

Subunit / interactions. Component of the NALCN channel complex. NALCN complex consists of NALCN and auxiliary subunits, UNC79, UNC80 and NACL1. These auxiliary subunits are essential for the NALCN channel function.

Subcellular location. Cell membrane.

Similarity. Belongs to the NALF family.

RefSeq proteins (1): NP_001073865* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR055288	NALCN_aux_factor_1/2	Family

UniProt features (27 total): disulfide bond 7, helix 6, strand 4, turn 3, transmembrane region 2, compositionally biased region 2, chain 1, region of interest 1, glycosylation site 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-B1AL88-F1	62.47	0.08

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 (7): 304–341, 324–377, 330–376, 334–361, 191–261, 226–313, 246–261

Glycosylation sites (1): 217

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 160 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_CALCIUM_ION_IMPORT, DACOSTA_UV_RESPONSE_VIA_ERCC3_TTD_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, CORRE_MULTIPLE_MYELOMA_UP, GOBP_REGULATION_OF_ACTION_POTENTIAL, GOBP_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_IMPORT_INTO_CELL, GOBP_REGULATION_OF_TRANSMISSION_OF_NERVE_IMPULSE

GO Biological Process (1): calcium ion import across plasma membrane (GO:0098703)

GO Molecular Function (1): stretch-activated, monoatomic cation-selective, calcium channel activity (GO:0015275)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion import	1
calcium ion transmembrane import into cytosol	1
inorganic cation import across plasma membrane	1
calcium ion import into cytosol	1
calcium channel activity	1
mechanosensitive monoatomic cation channel activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NALF1	UNC79	Q9P2D8	821
NALF1	UNC80	Q8N2C7	781
NALF1	NALCN	Q8IZF0	761
NALF1	ARHGAP15	Q53QZ3	583
NALF1	COLQ	Q9Y215	575
NALF1	PHGR1	C9JFL3	544
NALF1	TAFA2	Q8N3H0	529
NALF1	ARGLU1	Q9NWB6	434
NALF1	LAMB4	A4D0S4	432
NALF1	NAALADL2	Q58DX5	413
NALF1	GLRA3	O75311	398
NALF1	OR2B2	Q9GZK3	398
NALF1	SH3RF3	Q8TEJ3	376
NALF1	SLC35F3	Q8IY50	375
NALF1	CDH18	Q13634	370
NALF1	FAM185A	Q8N0U4	370

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CALM1	NALF1	psi-mi:“MI:0915”(physical association)	0.570

BioGRID (2): FAM155A (Positive Genetic), FAM155A (Affinity Capture-RNA)

ESM2 similar proteins: A0A088MLT8, A0JPH4, A2A8U2, A2ATD1, A6QLD2, B1AKI9, B1AL88, B3KU38, O14525, O35757, O75129, P0DPB3, P0DPB4, P12755, P17863, P27424, P49140, P55001, P55002, P85299, P97953, Q3V1G4, Q58CS8, Q5EGE1, Q5QQ56, Q5QQ57, Q60698, Q61137, Q68BL8, Q6DVA0, Q6L8S8, Q6L9W6, Q6S5C2, Q6ZWB6, Q80U62, Q80Z10, Q812A5, Q86Y38, Q8CCS2, Q8JG33

Diamond homologs: A2AWH2, A2BDP1, A4IFM1, A4IHZ3, B1AL88, O75949, Q8CCS2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	55
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3778949	NM_001080396.3(NALF1):c.916-258378_916-258377del	Pathogenic
3778959	NM_001080396.3(NALF1):c.916-265139_916-265138del	Pathogenic
3779442	NM_001080396.3(NALF1):c.916-258654_916-258653del	Pathogenic

SpliceAI

5952 predictions. Top by Δscore:

Variant	Effect	Δscore
13:107172527:A:AC	donor_gain	1.0000
13:107172528:C:CC	donor_gain	1.0000
13:107210578:CTGTA:C	donor_loss	1.0000
13:107210579:TGTA:T	donor_loss	1.0000
13:107210580:GTACC:G	donor_loss	1.0000
13:107210581:TAC:T	donor_loss	1.0000
13:107210582:ACCT:A	donor_loss	1.0000
13:107210583:CC:C	donor_loss	1.0000
13:107403879:CA:C	acceptor_gain	1.0000
13:107403880:A:C	acceptor_gain	1.0000
13:107541241:A:AC	donor_gain	1.0000
13:107541242:C:CC	donor_gain	1.0000
13:107170785:CC:C	acceptor_gain	0.9900
13:107170786:CC:C	acceptor_gain	0.9900
13:107170787:C:CC	acceptor_gain	0.9900
13:107172528:CA:C	donor_gain	0.9900
13:107172528:CAATA:C	donor_gain	0.9900
13:107210752:CAAT:C	acceptor_gain	0.9900
13:107210755:TCT:T	acceptor_loss	0.9900
13:107210756:C:CC	acceptor_gain	0.9900
13:107210757:T:C	acceptor_loss	0.9900
13:107249269:A:AC	donor_gain	0.9900
13:107249270:G:C	donor_gain	0.9900
13:107257079:C:CT	acceptor_gain	0.9900
13:107322630:T:TA	donor_gain	0.9900
13:107403878:CCA:C	acceptor_gain	0.9900
13:107403880:A:AC	acceptor_gain	0.9900
13:107693010:A:AC	donor_gain	0.9900
13:107693011:C:CC	donor_gain	0.9900
13:107702127:A:AT	donor_gain	0.9900

AlphaMissense

2984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:107210588:A:C	C361W	1.000
13:107210589:C:G	C361S	1.000
13:107210589:C:T	C361Y	1.000
13:107210590:A:G	C361R	1.000
13:107210590:A:T	C361S	1.000
13:107210594:G:C	F359L	1.000
13:107210594:G:T	F359L	1.000
13:107210595:A:C	F359C	1.000
13:107210596:A:G	F359L	1.000
13:107210642:A:C	F343L	1.000
13:107210642:A:T	F343L	1.000
13:107210644:A:G	F343L	1.000
13:107210648:A:C	C341W	1.000
13:107210649:C:G	C341S	1.000
13:107210649:C:T	C341Y	1.000
13:107210650:A:G	C341R	1.000
13:107210650:A:T	C341S	1.000
13:107210669:A:C	C334W	1.000
13:107210670:C:T	C334Y	1.000
13:107210671:A:G	C334R	1.000
13:107210732:A:C	C313W	1.000
13:107210733:C:T	C313Y	1.000
13:107210734:A:G	C313R	1.000
13:107210736:A:G	L312P	1.000
13:107210738:C:A	W311C	1.000
13:107210738:C:G	W311C	1.000
13:107210740:A:G	W311R	1.000
13:107210740:A:T	W311R	1.000
13:107865685:A:C	C304W	1.000
13:107865686:C:T	C304Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000001527 (13:107548205 A>C), RS1000007907 (13:107705012 T>G), RS1000014198 (13:107376208 C>A), RS1000014873 (13:107723342 G>A), RS1000020054 (13:107315854 G>A,T), RS1000022703 (13:107413180 T>C), RS1000023993 (13:107644180 A>C), RS1000028832 (13:107440327 T>C), RS1000031325 (13:107684047 G>A), RS1000033550 (13:107643931 T>A,G), RS1000035849 (13:107867584 G>A), RS1000039215 (13:107355628 T>C,G), RS1000043244 (13:107474028 T>A), RS1000044588 (13:107169107 C>T), RS1000045919 (13:107416154 C>T)

Disease associations

OMIM: gene MIM:619899 | disease phenotypes: MIM:260350

GenCC curated gene-disease

Mondo (2): BRCA2-related cancer predisposition (MONDO:0700269), familial pancreatic carcinoma (MONDO:0015278)

Orphanet (1): Familial pancreatic carcinoma (Orphanet:1333)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST000779_3	Depression (quantitative trait)	5.000000e-06
GCST000873_9	Anorexia nervosa	8.000000e-06
GCST001762_282	Obesity-related traits	7.000000e-06
GCST001762_707	Obesity-related traits	7.000000e-06
GCST001877_16	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	1.000000e-06
GCST002062_6	Reading and spelling	7.000000e-06
GCST002118_2	Metabolite levels (Pyroglutamine)	3.000000e-06
GCST002602_5	Vitamin D levels	2.000000e-06
GCST002900_4	Obesity in adult survivors of childhood cancer exposed to cranial radiation	3.000000e-08
GCST003434_7	Obsessive-compulsive symptoms	6.000000e-06
GCST004407_4	Neurocognitive impairment in HIV-1 infection (dichotomous)	2.000000e-06
GCST004641_4	Borderline personality disorder	8.000000e-06
GCST005351_15	Carboplatin disposition in epthelial ovarian cancer	5.000000e-06
GCST005352_9	Paclitaxel disposition in epithelial ovarian cancer	7.000000e-06
GCST005356_8	Severe malaria	6.000000e-07
GCST005357_4	Severe malaria (adjusted for sickle cell variant rs334)	3.000000e-06
GCST006088_40	Familial squamous cell lung carcinoma	7.000000e-07
GCST006218_102	Erosive tooth wear (severe vs non-severe)	1.000000e-06
GCST006304_13	Irritable bowel syndrome	5.000000e-06
GCST006479_113	Diverticular disease	5.000000e-12
GCST006479_114	Diverticular disease	2.000000e-09
GCST007576_221	Chronotype	4.000000e-08
GCST008105_3	Diverticular disease	1.000000e-13
GCST008163_200	Height	2.000000e-07
GCST008256_7	Diverticulitis	5.000000e-08
GCST008256_8	Diverticulitis	2.000000e-07
GCST008257_3	Diverticular disease	1.000000e-08
GCST008522_61	Bitter alcoholic beverage consumption	9.000000e-07
GCST009439_6	Age-related cognitive decline (language) (slope of z-scores)	7.000000e-06
GCST010796_4539	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0005106	body composition measurement
EFO:0005301	reading and spelling ability
EFO:0005408	pyroglutamine measurement
EFO:0007802	obsessive-compulsive symptom measurement
EFO:0007998	cognitive impairment measurement
EFO:0006953	family history of lung cancer
EFO:0009959	diverticular disease
EFO:0008328	chronotype measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0007710	cognitive decline measurement
EFO:0004327	electrocardiography
EFO:0007828	daytime rest measurement
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535837	Pancreatic carcinoma, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, increases expression	3
entinostat	affects cotreatment, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, affects methylation	1
sodium arsenite	decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Methapyrilene	affects methylation	1
Silicon Dioxide	increases expression	1
Triclosan	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Cadmium Chloride	increases expression, increases abundance	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00835133	Not specified	ACTIVE_NOT_RECRUITING	Collecting Blood and Tissue Samples From Family Members of Patients With Pancreatic Diseases, Pancreatic Cancer, and Melanoma
NCT02070705	Not specified	TERMINATED	DCE MRI in Patients With Pancreatic Cancer
NCT02078245	Not specified	UNKNOWN	Quality Control Study of MR Based Screening of Individual With Increased Risk for Pancreas Cancer.
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT02560896	Not specified	COMPLETED	Understanding Genetic Incidental Findings in Your Family (UNIFY Study)
NCT03693378	Not specified	COMPLETED	A Study of IMMray™ PanCan-d Test for Early Detection of Pancreatic Cancer in High-risk Groups
NCT04095195	Not specified	RECRUITING	Registry of Subjects at Risk of Pancreatic Cancer
NCT04104230	Not specified	UNKNOWN	Quebec Pancreas Cancer Study
NCT04247503	Not specified	ACTIVE_NOT_RECRUITING	Cohort Study of Pancreatic Cancer Risk
NCT04743479	Not specified	RECRUITING	Artificial Intelligence-based Early Screening of Pancreatic Cancer and High Risk Tracing (ESPRIT-AI)
NCT05740111	Not specified	ENROLLING_BY_INVITATION	The PREPAIRD Study: Personalized Surveillance for Early Detection of Pancreatic Cancer in High Risk Individuals
NCT06760741	Not specified	NOT_YET_RECRUITING	PREVENPANC Project: a Spanish Multicenter Study for Pancreatic Cancer Prevention
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer