PACC1

Summary

PACC1 (proton activated chloride channel 1, HGNC:25593) is a protein-coding gene on chromosome 1q32.3, encoding Proton-activated chloride channel (Q9H813). Chloride channel gated by pH that facilitates the entry of chloride ions into cells upon exposure to extracellular acidic pH.

Enables pH-gated chloride channel activity. Involved in chloride transport. Located in plasma membrane.

Source: NCBI Gene 55248 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_018252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25593
Approved symbol	PACC1
Name	proton activated chloride channel 1
Location	1q32.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10874, PAC, ASOR, PAORAC
Ensembl gene	ENSG00000065600
Ensembl biotype	protein_coding
OMIM	618427
Entrez	55248

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000261455, ENST00000467822, ENST00000471937, ENST00000478166, ENST00000535273, ENST00000890971, ENST00000890972, ENST00000890973, ENST00000890974, ENST00000921366, ENST00000921367, ENST00000921368, ENST00000921369, ENST00000921370, ENST00000921371, ENST00000960795

RefSeq mRNA: 5 — MANE Select: NM_018252 NM_001198862, NM_001377478, NM_001377479, NM_001377480, NM_018252

CCDS: CCDS1504, CCDS55687

Canonical transcript exons

ENST00000261455 — 8 exons

Exon	Start	End
ENSE00001010450	212375193	212375300
ENSE00001162856	212363928	212365376
ENSE00003570815	212379895	212380037
ENSE00003580816	212386891	212387100
ENSE00003590563	212385274	212385425
ENSE00003605747	212410425	212410521
ENSE00003656453	212377562	212377706
ENSE00003658107	212414722	212414886

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 95.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.3655 / max 176.1941, expressed in 1761 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17377	12.3655	1761

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	95.17	gold quality
spinal cord	UBERON:0002240	94.42	gold quality
inferior vagus X ganglion	UBERON:0005363	94.02	gold quality
corpus callosum	UBERON:0002336	92.03	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.87	gold quality
secondary oocyte	CL:0000655	91.86	gold quality
pons	UBERON:0000988	91.46	gold quality
subthalamic nucleus	UBERON:0001906	90.60	gold quality
medial globus pallidus	UBERON:0002477	90.44	gold quality
cortical plate	UBERON:0005343	90.30	gold quality
endothelial cell	CL:0000115	89.92	gold quality
globus pallidus	UBERON:0001875	89.62	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.28	gold quality
superior vestibular nucleus	UBERON:0007227	87.85	gold quality
ventricular zone	UBERON:0003053	87.04	gold quality
ganglionic eminence	UBERON:0004023	86.93	gold quality
monocyte	CL:0000576	86.64	gold quality
oocyte	CL:0000023	86.58	gold quality
mononuclear cell	CL:0000842	86.31	gold quality
leukocyte	CL:0000738	85.93	gold quality
midbrain	UBERON:0001891	84.64	gold quality
substantia nigra pars compacta	UBERON:0001965	84.40	gold quality
prefrontal cortex	UBERON:0000451	84.38	gold quality
substantia nigra	UBERON:0002038	84.30	gold quality
ventral tegmental area	UBERON:0002691	84.27	gold quality
lateral globus pallidus	UBERON:0002476	83.82	gold quality
dorsal plus ventral thalamus	UBERON:0001897	83.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.54	gold quality
Ammon’s horn	UBERON:0001954	83.41	gold quality
granulocyte	CL:0000094	82.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting PACC1, 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-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-325	99.58	66.55	358
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-92B-5P	99.36	63.29	110

Literature-anchored findings (GeneRIF, showing 5)

• PAC (TMEM206) was indentified as being essential for the widely observed proton-activated Cl- (PAC) currents (ICl,H). (PMID:31023925)
• PACC1 encodes a new type of chloride channel activated by acid or proton; its wide expression suggests a broad role for this conserved chloride channel in physiological and pathological processes associated with acidic pH. (PMID:31023925)
• Structures and pH-sensing mechanism of the proton-activated chloride channel. (PMID:33149300)
• Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206. (PMID:37468723)
• Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells. (PMID:38627262)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pacc1	ENSDARG00000012271
mus_musculus	Pacc1	ENSMUSG00000026627
rattus_norvegicus	Pacc1	ENSRNOG00000003915

Protein

Protein identifiers

Proton-activated chloride channel — Q9H813 (reviewed: Q9H813)

Alternative names: Acid-sensitive outwardly-rectifying anion channel, Proton-activated outwardly rectifying anion channel, Transmembrane protein 206

All UniProt accessions (1): Q9H813

UniProt curated annotations — full annotation on UniProt →

Function. Chloride channel gated by pH that facilitates the entry of chloride ions into cells upon exposure to extracellular acidic pH. Involved in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed, with highest expression in brain.

Post-translational modifications. N-glycosylated.

Similarity. Belongs to the proton-activated chloride channel family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H813-1	1	yes
Q9H813-2	2

RefSeq proteins (5): NP_001185791, NP_001364407, NP_001364408, NP_001364409, NP_060722* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029366	TMEM206	Family

Pfam: PF15122

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (40 total): strand 14, helix 5, sequence conflict 4, modified residue 4, topological domain 3, glycosylation site 2, transmembrane region 2, turn 2, chain 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7SQH	ELECTRON MICROSCOPY	2.5
7SQG	ELECTRON MICROSCOPY	2.6
8FBL	ELECTRON MICROSCOPY	2.7
8EQ4	ELECTRON MICROSCOPY	2.71
8ZLL	ELECTRON MICROSCOPY	2.89
7SQF	ELECTRON MICROSCOPY	3.1
9LHM	ELECTRON MICROSCOPY	3.43
7JNA	ELECTRON MICROSCOPY	3.6
9LI2	ELECTRON MICROSCOPY	3.72
7JNC	ELECTRON MICROSCOPY	3.73
8ZLB	ELECTRON MICROSCOPY	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H813-F1	79.40	0.43

Functional residue map

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

Post-translational modifications (4): 9, 10, 14, 24

Glycosylation sites (2): 155, 162

Mutagenesis-validated functional residues (1):

Position	Phenotype
307	reduced i(-) permeability.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 129 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, PATIL_LIVER_CANCER, GOBP_CHLORIDE_TRANSPORT, MODULE_239, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_DN, PU1_Q6, ELK1_01, P300_01, DOUGLAS_BMI1_TARGETS_UP, RGAGGAARY_PU1_Q6, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR

GO Biological Process (4): chloride transport (GO:0006821), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (3): pH-gated chloride channel activity (GO:0061797), chloride channel activity (GO:0005254), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), cell surface (GO:0009986), chloride channel complex (GO:0034707), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
monoatomic anion transport	1
inorganic anion transport	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
pH-gated monoatomic ion channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1

Protein interactions and networks

STRING

796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PACC1	TECRL	Q5HYJ1	720
PACC1	ASGR1	P07306	706
PACC1	DMBT1	Q9UGM3	632
PACC1	ESCO1	Q5FWF5	607
PACC1	ESCO2	Q56NI9	606
PACC1	GOLPH3	Q9H4A6	578
PACC1	NOMO2	Q5JPE7	570
PACC1	TMEM97	Q5BJF2	566
PACC1	AKT1	P31749	561
PACC1	NOMO3	P69849	544
PACC1	NOMO1	P78421	528
PACC1	LGALS4	P56470	506
PACC1	PRND	Q9UKY0	460
PACC1	FCF1	Q9Y324	447
PACC1	PDZK1IP1	Q13113	446

IntAct

40 interactions, top by confidence:

A	B	Type	Score
TMEM147	PACC1	psi-mi:“MI:0915”(physical association)	0.740
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
PACC1	PLLP	psi-mi:“MI:0915”(physical association)	0.560
PLP2	PACC1	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	PACC1	psi-mi:“MI:0915”(physical association)	0.560
CTXN3	PACC1	psi-mi:“MI:0915”(physical association)	0.560
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
ASIC4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
PACC1	DEGS1	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
	NPC1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
HLA-DRA	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NRSN1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
PACC1	TNPO2	psi-mi:“MI:0914”(association)	0.350
PACC1	ATP1A3	psi-mi:“MI:0914”(association)	0.350
BZW2	GOLIM4	psi-mi:“MI:0914”(association)	0.350
NUDT9	POF1B	psi-mi:“MI:0914”(association)	0.350
PACC1	IPO5	psi-mi:“MI:0914”(association)	0.350
SCN3B	NBAS	psi-mi:“MI:0914”(association)	0.350
ZNF843	PMPCA	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMEM147	PACC1	psi-mi:“MI:0915”(physical association)	0.000
CTXN3	PACC1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (193): TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM206 (Affinity Capture-MS), TMEM147 (Affinity Capture-MS), NOP9 (Affinity Capture-MS), DCUN1D5 (Affinity Capture-MS), KNTC1 (Affinity Capture-MS), WDR3 (Affinity Capture-MS), GNPAT (Affinity Capture-MS)

ESM2 similar proteins: A0A0K8RK34, A0A7H0DND3, A8WH72, A8WUV1, C0HKG1, G1CWH5, G5EBL2, G5ECI1, H2KZM6, O36400, O45201, O76411, P03205, P0C6Z5, P13374, P17634, P18475, P18535, P21063, P24872, P26305, P34259, P34292, P34312, P45442, P52881, P86899, Q07FZ2, Q0IHD6, Q10128, Q10952, Q1HVG2, Q20924, Q5FVR3, Q66653, Q6DE06, Q77MP7, Q86NG3, Q8BJ83, Q93118

Diamond homologs: Q0IHD6, Q0V9Z3, Q2KHV2, Q5RDP8, Q66H28, Q7SY31, Q9D771, Q9H813

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1640 predictions. Top by Δscore:

Variant	Effect	Δscore
1:212375296:CTTGT:C	acceptor_gain	1.0000
1:212379889:GCCCA:G	donor_loss	1.0000
1:212379890:CCCA:C	donor_loss	1.0000
1:212379891:CCA:C	donor_loss	1.0000
1:212379892:CA:C	donor_loss	1.0000
1:212379893:ACCT:A	donor_loss	1.0000
1:212379894:CCTT:C	donor_loss	1.0000
1:212379955:CTA:C	donor_gain	1.0000
1:212379955:CTACT:C	donor_gain	1.0000
1:212380035:TTT:T	acceptor_gain	1.0000
1:212380036:TT:T	acceptor_gain	1.0000
1:212380036:TTCTG:T	acceptor_loss	1.0000
1:212380037:TC:T	acceptor_loss	1.0000
1:212380038:C:CA	acceptor_loss	1.0000
1:212380039:T:A	acceptor_loss	1.0000
1:212385423:TAC:T	acceptor_gain	1.0000
1:212385427:T:A	acceptor_loss	1.0000
1:212386914:T:TA	donor_gain	1.0000
1:212386955:A:AC	donor_gain	1.0000
1:212386956:C:CC	donor_gain	1.0000
1:212387098:GGC:G	acceptor_gain	1.0000
1:212387099:GC:G	acceptor_gain	1.0000
1:212387100:CC:C	acceptor_gain	1.0000
1:212387101:C:CC	acceptor_gain	1.0000
1:212410421:TCA:T	donor_loss	1.0000
1:212410423:A:C	donor_loss	1.0000
1:212410424:C:T	donor_loss	1.0000
1:212410517:CTCAG:C	acceptor_gain	1.0000
1:212410518:TCAG:T	acceptor_gain	1.0000
1:212410519:CAG:C	acceptor_gain	1.0000

AlphaMissense

2324 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:212375225:A:G	W287R	0.993
1:212375225:A:T	W287R	0.993
1:212375223:C:A	W287C	0.989
1:212375223:C:G	W287C	0.989
1:212365287:A:C	S327R	0.988
1:212365287:A:T	S327R	0.988
1:212365289:T:G	S327R	0.988
1:212377571:G:C	F258L	0.987
1:212377571:G:T	F258L	0.987
1:212377573:A:G	F258L	0.987
1:212379973:A:G	F187S	0.986
1:212375229:A:C	F285L	0.985
1:212375229:A:T	F285L	0.985
1:212375231:A:G	F285L	0.985
1:212379945:G:C	F196L	0.985
1:212379945:G:T	F196L	0.985
1:212379947:A:G	F196L	0.985
1:212377637:G:C	F236L	0.984
1:212377637:G:T	F236L	0.984
1:212377639:A:G	F236L	0.984
1:212377649:G:C	F232L	0.984
1:212377649:G:T	F232L	0.984
1:212377651:A:G	F232L	0.984
1:212377572:A:G	F258S	0.982
1:212365297:G:T	A324D	0.981
1:212379921:G:C	F204L	0.981
1:212379921:G:T	F204L	0.981
1:212379923:A:G	F204L	0.981
1:212379972:G:C	F187L	0.981
1:212379972:G:T	F187L	0.981

dbSNP variants (sampled 300 via entrez): RS1000023946 (1:212384738 T>C), RS1000120471 (1:212390786 G>T), RS1000257027 (1:212411620 T>C), RS1000305373 (1:212365020 C>T), RS1000377120 (1:212379194 T>C), RS1000389527 (1:212371717 A>G), RS1000408863 (1:212390606 G>A,C), RS1000446425 (1:212403699 G>T), RS1000527922 (1:212373995 C>T), RS1000590991 (1:212408569 C>A,G,T), RS1000682182 (1:212380903 C>G), RS1000748076 (1:212379410 C>T), RS1000841972 (1:212395724 C>T), RS1000887465 (1:212400967 T>C), RS1000893045 (1:212407235 A>G)

Disease associations

OMIM: gene MIM:618427 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004618_26	White blood cell count (basophil)	2.000000e-14
GCST004631_47	Basophil percentage of white cells	8.000000e-15
GCST004634_6	Basophil percentage of granulocytes	1.000000e-16
GCST90002379_18	Basophil count	3.000000e-09
GCST90002379_19	Basophil count	1.000000e-21
GCST90002380_122	Basophil percentage of white cells	9.000000e-26

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Valproic Acid	affects expression, decreases methylation, increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
lead acetate	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
arsenite	affects binding, increases reaction	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
ICG 001	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methotrexate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7H6	Ubigene HEK293T PACC1 KO	Transformed cell line	Female
CVCL_D9M4	Ubigene HEK293 PACC1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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