ASIC4

Summary

ASIC4 (acid sensing ion channel subunit family member 4, HGNC:21263) is a protein-coding gene on chromosome 2q35, encoding Acid-sensing ion channel 4 (Q96FT7). Does not exhibit measurable stand-alone pH-gated sodium channel activity but may form pH-gated heterotrimeric sodium channels.

This gene belongs to the superfamily of acid-sensing ion channels, which are proton-gated, amiloride-sensitive sodium channels. These channels have been implicated in synaptic transmission, pain perception as well as mechanoperception. This gene is predominantly expressed in the pituitary gland, and was considered a candidate for paroxysmal dystonic choreoathetosis (PDC), a movement disorder, however, no correlation was found between mutations in this gene and PDC.

Source: NCBI Gene 55515 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 13 total
• MANE Select transcript: NM_018674

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21263
Approved symbol	ASIC4
Name	acid sensing ion channel subunit family member 4
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	BNAC4
Ensembl gene	ENSG00000072182
Ensembl biotype	protein_coding
OMIM	606715
Entrez	55515

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000347842, ENST00000358078, ENST00000461395, ENST00000473709, ENST00000474489, ENST00000693692

RefSeq mRNA: 2 — MANE Select: NM_018674 NM_018674, NM_182847

CCDS: CCDS2442, CCDS33384

Canonical transcript exons

ENST00000358078 — 10 exons

Exon	Start	End
ENSE00000786129	219537632	219537736
ENSE00001181728	219514482	219515306
ENSE00001331872	219537933	219538772
ENSE00002392208	219537242	219537321
ENSE00003512191	219532883	219532939
ENSE00003548274	219537066	219537157
ENSE00003550735	219531758	219531902
ENSE00003577635	219532315	219532477
ENSE00003586548	219535171	219535324
ENSE00003673055	219532001	219532128

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 88.63.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1418 / max 125.7250, expressed in 232 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25518	1.2462	151
25519	0.4440	93
25517	0.3991	170
202577	0.0524	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	88.63	gold quality
adenohypophysis	UBERON:0002196	86.75	gold quality
vena cava	UBERON:0004087	82.67	gold quality
type B pancreatic cell	CL:0000169	82.00	gold quality
cerebellar hemisphere	UBERON:0002245	80.74	gold quality
olfactory bulb	UBERON:0002264	80.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.74	gold quality
cerebellar cortex	UBERON:0002129	80.45	gold quality
amygdala	UBERON:0001876	80.35	gold quality
cerebellum	UBERON:0002037	79.49	gold quality
cingulate cortex	UBERON:0003027	79.05	gold quality
anterior cingulate cortex	UBERON:0009835	79.00	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.65	silver quality
tongue squamous epithelium	UBERON:0006919	78.50	gold quality
body of tongue	UBERON:0011876	77.45	gold quality
pons	UBERON:0000988	77.00	gold quality
right frontal lobe	UBERON:0002810	76.94	gold quality
hypothalamus	UBERON:0001898	76.46	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.45	gold quality
substantia nigra	UBERON:0002038	75.96	gold quality
tongue	UBERON:0001723	75.91	gold quality
nucleus accumbens	UBERON:0001882	75.86	gold quality
midbrain	UBERON:0001891	75.84	gold quality
prefrontal cortex	UBERON:0000451	75.68	gold quality
gluteal muscle	UBERON:0002000	75.40	silver quality
brain	UBERON:0000955	75.07	gold quality
temporal lobe	UBERON:0001871	75.04	gold quality
triceps brachii	UBERON:0001509	74.96	gold quality
cardia of stomach	UBERON:0001162	74.91	gold quality
forebrain	UBERON:0001890	74.79	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	31.77
E-GEOD-137537	yes	17.58
E-ANND-3	yes	3.11

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Data show that transfected ASIC4 is targeted to the plasma membrane in CHO-K1 cells, where it associates with ASIC1a and downregulates exogenous ASIC1a expression. (PMID:18662336)
• Acid-sensing ion channel (ASIC) 4 predominantly localizes to an early endosome-related organelle upon heterologous expression (PMID:26667795)

Cross-species orthologs

28 orthologs

Organism	Symbol	Gene ID
danio_rerio	asic4b	ENSDARG00000004243
danio_rerio	asic4a	ENSDARG00000025162
mus_musculus	Asic4	ENSMUSG00000033007
rattus_norvegicus	Asic4	ENSRNOG00000019985
drosophila_melanogaster	Nach	FBGN0024319
drosophila_melanogaster	ppk28	FBGN0030795
drosophila_melanogaster	ppk17	FBGN0032602
drosophila_melanogaster	ppk6	FBGN0034489
drosophila_melanogaster	ppk12	FBGN0034730
drosophila_melanogaster	ppk29	FBGN0034965
drosophila_melanogaster	ppk24	FBGN0039839
drosophila_melanogaster	ppk22	FBGN0051105
drosophila_melanogaster	ppk8	FBGN0052792
drosophila_melanogaster	ppk5	FBGN0053289
drosophila_melanogaster	ppk16	FBGN0065108
drosophila_melanogaster	ppk11	FBGN0065109
drosophila_melanogaster	ppk9	FBGN0085398
drosophila_melanogaster	ppk18	FBGN0265001
caenorhabditis_elegans		WBGENE00003168
caenorhabditis_elegans		WBGENE00003174
caenorhabditis_elegans		WBGENE00007518
caenorhabditis_elegans		WBGENE00009073
caenorhabditis_elegans		WBGENE00011891
caenorhabditis_elegans	delm-2	WBGENE00016063
caenorhabditis_elegans	acd-1	WBGENE00016064
caenorhabditis_elegans	acd-2	WBGENE00016066
caenorhabditis_elegans		WBGENE00016699
caenorhabditis_elegans		WBGENE00017879

Paralogs (8): ASIC2 (ENSG00000108684), ASIC1 (ENSG00000110881), SCNN1A (ENSG00000111319), SCNN1D (ENSG00000162572), SCNN1G (ENSG00000166828), SCNN1B (ENSG00000168447), ASIC3 (ENSG00000213199), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Acid-sensing ion channel 4 — Q96FT7 (reviewed: Q96FT7)

Alternative names: Amiloride-sensitive cation channel 4, Amiloride-sensitive cation channel 4, pituitary

All UniProt accessions (2): Q96FT7, A0A8I5KPF5

UniProt curated annotations — full annotation on UniProt →

Function. Does not exhibit measurable stand-alone pH-gated sodium channel activity but may form pH-gated heterotrimeric sodium channels. Its activity could also depend on alternative gating mechanisms.

Subunit / interactions. Homotrimer. Heterotrimer; with other ASIC proteins producing functional channels.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in pituitary gland. Weakly expressed in brain, vestibular system and organ of Corti.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96FT7-4	3	yes
Q96FT7-1	1
Q96FT7-2	2

RefSeq proteins (2): NP_061144, NP_878267 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001873	ENaC	Family
IPR020903	ENaC_CS	Conserved_site

Pfam: PF00858

UniProt features (24 total): disulfide bond 7, topological domain 3, glycosylation site 3, splice variant 3, sequence variant 3, transmembrane region 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FT7-F1	80.37	0.52

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): 118–202, 180–187, 296–375, 318–371, 322–369, 331–353, 333–345

Glycosylation sites (3): 376, 191, 243

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: 87 (showing top): GOBP_BEHAVIOR, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, AREB6_03, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_FEAR_RESPONSE, HP1SITEFACTOR_Q6, NKX22_01, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, SHEN_SMARCA2_TARGETS_DN, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_GATED_CHANNEL_ACTIVITY, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_CATION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (5): behavioral fear response (GO:0001662), sodium ion transmembrane transport (GO:0035725), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (3): ligand-gated sodium channel activity (GO:0015280), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), 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
behavioral defense response	1
fear response	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
sodium channel activity	1
ligand-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
sodium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

664 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASIC4	PNKD	Q8N490	890
ASIC4	HAGH	Q16775	767
ASIC4	ASIC2	Q16515	699
ASIC4	ASIC3	Q9UHC3	699
ASIC4	SLC4A3	P48751	640
ASIC4	TRPV1	Q8NER1	564
ASIC4	EHBP1L1	Q8N3D4	509
ASIC4	BUD13	Q9BRD0	486
ASIC4	CAMTA1	Q9Y6Y1	458
ASIC4	ZPR1	O75312	449
ASIC4	APOA5	Q6Q788	425
ASIC4	TNFSF10	P50591	414
ASIC4	GPR65	Q8IYL9	414
ASIC4	GPR4	P46093	400
ASIC4	TRPV4	Q9HBA0	383

IntAct

10 interactions, top by confidence:

A	B	Type	Score
OTX2	ASIC4	psi-mi:“MI:0915”(physical association)	0.560
ASIC4		psi-mi:“MI:0915”(physical association)	0.400
CFTR	ASIC4	psi-mi:“MI:0915”(physical association)	0.370
ASIC4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	CLGN	psi-mi:“MI:0914”(association)	0.350
ASIC4	OTX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (167): ASIC4 (Two-hybrid), HSPA14 (Affinity Capture-MS), TMEM8A (Affinity Capture-MS), ADCY3 (Affinity Capture-MS), TMEM231 (Affinity Capture-MS), CNNM1 (Affinity Capture-MS), ITPRIP (Affinity Capture-MS), ABCA3 (Affinity Capture-MS), LRP12 (Affinity Capture-MS), GABRB3 (Affinity Capture-MS), CLPTM1 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), TSPAN6 (Affinity Capture-MS), GLB1L2 (Affinity Capture-MS), ALG9 (Affinity Capture-MS)

ESM2 similar proteins: A0A287A2K5, F1MV99, O08858, O43193, O77808, O97772, P28646, P30098, P30552, P30553, P30796, P30872, P30873, P30937, P30938, P31391, P32239, P32300, P32307, P32745, P33533, P35346, P35370, P35377, P41143, P41146, P46095, P46627, P47748, P48044, P49660, P51651, P56481, P58406, P79266, P79292, Q49LX5, Q5D0K2, Q6W5G4, Q6YNI2

Diamond homologs: O35240, P55926, P78348, Q10025, Q16515, Q1XA76, Q62962, Q6NXK8, Q6X1Y6, Q708S3, Q708S4, Q708S5, Q708S6, Q708S7, Q708S8, Q7T1N4, Q7TNS7, Q925H0, Q96FT7, Q9JHS6, Q9NY37, Q9R0W5, Q9R0Y1, Q9UHC3, Q25011, H1AFJ5, H2Q5A1, H9GBX2, K7GET2, O13263, O97741, P24585, P24612, P34886, P37088, P37089, P51169, P51171, P51172, Q09274

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1894 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219515304:GTG:G	donor_gain	1.0000
2:219531872:G:GT	donor_gain	1.0000
2:219531895:G:GT	donor_gain	1.0000
2:219531898:GACAA:G	donor_gain	1.0000
2:219531903:G:GG	donor_gain	1.0000
2:219531916:A:T	donor_gain	1.0000
2:219531921:G:T	donor_gain	1.0000
2:219532125:GCGG:G	donor_gain	1.0000
2:219532126:CGGGT:C	donor_loss	1.0000
2:219532127:GG:G	donor_gain	1.0000
2:219532127:GGGT:G	donor_loss	1.0000
2:219532128:GG:G	donor_gain	1.0000
2:219532129:GTGA:G	donor_loss	1.0000
2:219532130:T:G	donor_loss	1.0000
2:219537153:GCTGG:G	donor_gain	1.0000
2:219537156:GG:G	donor_gain	1.0000
2:219537157:GG:G	donor_gain	1.0000
2:219537158:G:GG	donor_gain	1.0000
2:219537158:GTG:G	donor_loss	1.0000
2:219537159:T:A	donor_loss	1.0000
2:219537236:TCCCA:T	acceptor_loss	1.0000
2:219537239:CAG:C	acceptor_loss	1.0000
2:219537240:A:AC	acceptor_loss	1.0000
2:219537240:A:AG	acceptor_gain	1.0000
2:219537241:G:GG	acceptor_gain	1.0000
2:219537241:G:GT	acceptor_loss	1.0000
2:219537241:GGA:G	acceptor_gain	1.0000
2:219537597:T:A	acceptor_gain	1.0000
2:219515304:GTGGT:G	donor_loss	0.9900
2:219515305:TG:T	donor_gain	0.9900

AlphaMissense

4295 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:219515068:T:A	V242D	1.000
2:219515076:T:A	C245S	1.000
2:219515076:T:C	C245R	1.000
2:219515077:G:A	C245Y	1.000
2:219515077:G:C	C245S	1.000
2:219515077:G:T	C245F	1.000
2:219515078:C:G	C245W	1.000
2:219515081:T:A	N246K	1.000
2:219515081:T:G	N246K	1.000
2:219515087:C:A	N248K	1.000
2:219515087:C:G	N248K	1.000
2:219515131:T:C	L263P	1.000
2:219515227:G:C	R295P	1.000
2:219515263:G:A	C307Y	1.000
2:219515264:C:G	C307W	1.000
2:219515299:T:G	F319C	1.000
2:219531773:G:T	G327W	1.000
2:219531774:G:A	G327E	1.000
2:219531774:G:T	G327V	1.000
2:219531779:T:A	C329S	1.000
2:219531779:T:C	C329R	1.000
2:219531780:G:A	C329Y	1.000
2:219531780:G:C	C329S	1.000
2:219531780:G:T	C329F	1.000
2:219531781:T:G	C329W	1.000
2:219531789:T:C	F332S	1.000
2:219531846:T:C	L351P	1.000
2:219531858:T:C	L355P	1.000
2:219531892:G:C	W366C	1.000
2:219531892:G:T	W366C	1.000

dbSNP variants (sampled 300 via entrez): RS1000076930 (2:219519223 G>A), RS1000274658 (2:219509129 A>T), RS1000338083 (2:219531348 A>T), RS1000365468 (2:219524771 C>A,T), RS1000366696 (2:219521066 C>G), RS1000439878 (2:219515879 C>T), RS1000461830 (2:219522419 A>C,G), RS1000525302 (2:219517920 G>A), RS1000629898 (2:219507070 AT>A), RS1000658935 (2:219527377 G>A), RS1000699157 (2:219523332 C>T), RS1000784527 (2:219535489 T>C), RS1000876854 (2:219530962 G>A), RS1001078362 (2:219530016 C>G,T), RS1001192475 (2:219535274 C>G)

Disease associations

OMIM: gene MIM:606715 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007429_71	Lung function (FVC)	3.000000e-10
GCST009246_131	Cerebrospinal fluid sTREM-2 levels	4.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0010151	soluble triggering receptor expressed on myeloid cells 2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenite	increases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Toluene	decreases expression, increases methylation	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1

Clinical trials (associated diseases)

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