CNIH2

Summary

CNIH2 (cornichon family AMPA receptor auxiliary protein 2, HGNC:28744) is a protein-coding gene on chromosome 11q13.2, encoding Protein cornichon homolog 2 (Q6PI25). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs).

The protein encoded by this gene is an auxiliary subunit of the ionotropic glutamate receptor of the AMPA subtype. AMPA receptors mediate fast synaptic neurotransmission in the central nervous system. This protein has been reported to interact with the Type I AMPA receptor regulatory protein isoform gamma-8 to control assembly of hippocampal AMPA receptor complexes, thereby modulating receptor gating and pharmacology. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 254263 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_182553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28744
Approved symbol	CNIH2
Name	cornichon family AMPA receptor auxiliary protein 2
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC50896, Cnil, CNIH-2
Ensembl gene	ENSG00000174871
Ensembl biotype	protein_coding
OMIM	611288
Entrez	254263

Gene structure

Transcript identifiers

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

ENST00000311445, ENST00000528063, ENST00000528852, ENST00000530519, ENST00000531936, ENST00000534826

RefSeq mRNA: 1 — MANE Select: NM_182553 NM_182553

CCDS: CCDS8131

Canonical transcript exons

ENST00000311445 — 6 exons

Exon	Start	End
ENSE00001337122	66283570	66284206
ENSE00002192226	66278175	66278537
ENSE00003468199	66283035	66283147
ENSE00003571256	66283248	66283391
ENSE00003644459	66282259	66282327
ENSE00003654728	66282733	66282780

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 99.17.

FANTOM5 (CAGE): breadth broad, TPM avg 10.1539 / max 490.0400, expressed in 834 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115313	9.9942	827
115316	0.0842	54
115314	0.0448	26
115315	0.0307	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.17	gold quality
ganglionic eminence	UBERON:0004023	98.52	gold quality
anterior cingulate cortex	UBERON:0009835	97.63	gold quality
right frontal lobe	UBERON:0002810	97.30	gold quality
nucleus accumbens	UBERON:0001882	96.44	gold quality
caudate nucleus	UBERON:0001873	96.31	gold quality
prefrontal cortex	UBERON:0000451	96.15	gold quality
amygdala	UBERON:0001876	96.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.01	gold quality
putamen	UBERON:0001874	95.34	gold quality
islet of Langerhans	UBERON:0000006	95.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.92	gold quality
hypothalamus	UBERON:0001898	94.77	gold quality
neocortex	UBERON:0001950	93.64	gold quality
frontal cortex	UBERON:0001870	93.18	gold quality
Ammon’s horn	UBERON:0001954	93.08	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.98	gold quality
cerebral cortex	UBERON:0000956	92.61	gold quality
ventricular zone	UBERON:0003053	92.25	gold quality
forebrain	UBERON:0001890	92.23	gold quality
cerebellar hemisphere	UBERON:0002245	91.67	gold quality
cerebellar cortex	UBERON:0002129	91.59	gold quality
adenohypophysis	UBERON:0002196	91.36	gold quality
pituitary gland	UBERON:0000007	91.26	gold quality
brain	UBERON:0000955	91.26	gold quality
cerebellum	UBERON:0002037	89.94	gold quality
temporal lobe	UBERON:0001871	89.14	gold quality
substantia nigra	UBERON:0002038	87.39	gold quality
pancreatic ductal cell	CL:0002079	85.99	silver quality
midbrain	UBERON:0001891	84.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting CNIH2, 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-4673	100.00	66.64	1490
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3679-3P	99.64	69.88	1599

Literature-anchored findings (GeneRIF, showing 2)

• Significant upregulation of CNIH-2 mRNA expression was found in schizophrenia. (PMID:23103966)
• CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression. (PMID:38718887)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnih2	ENSDARG00000043662
mus_musculus	Cnih2	ENSMUSG00000024873
rattus_norvegicus	Cnih2	ENSRNOG00000020247
drosophila_melanogaster	cni	FBGN0000339
caenorhabditis_elegans		WBGENE00011648

Paralogs (4): CNIH1 (ENSG00000100528), PPCS (ENSG00000127125), CNIH4 (ENSG00000143771), CNIH3 (ENSG00000143786)

Protein

Protein identifiers

Protein cornichon homolog 2 — Q6PI25 (reviewed: Q6PI25)

Alternative names: Cornichon family AMPA receptor auxiliary protein 2, Cornichon-like protein

All UniProt accessions (4): Q6PI25, E9PIT8, E9PJQ8, E9PS15

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by regulating their rates of activation, deactivation and desensitization. Blocks CACNG8-mediated resensitization of AMPA receptors.

Subunit / interactions. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACGN8. Interacts with GRIA1. Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, DLG4 and CACNG8.

Subcellular location. Endoplasmic reticulum membrane. Postsynaptic cell membrane. Cell projection. Dendrite. Dendritic spine. Postsynaptic density.

Tissue specificity. Expression is up-regulated in dorsolateral prefrontal cortex of patients with schizophrenia (postmortem brain study).

Similarity. Belongs to the cornichon family.

RefSeq proteins (1): NP_872359* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003377	Cornichon	Family
IPR033466	Cornichon_conserved	Conserved_site

Pfam: PF03311

UniProt features (16 total): helix 5, topological domain 4, strand 3, transmembrane region 3, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8SS7	ELECTRON MICROSCOPY	2.76
8SS6	ELECTRON MICROSCOPY	3.01
8SS3	ELECTRON MICROSCOPY	3.21
8SS4	ELECTRON MICROSCOPY	3.3
8SS2	ELECTRON MICROSCOPY	3.58
8SSB	ELECTRON MICROSCOPY	3.66
8SSA	ELECTRON MICROSCOPY	3.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PI25-F1	87.86	0.61

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-5694530	Cargo concentration in the ER

MSigDB gene sets: 183 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, RNGTGGGC_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AP4_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, chr11q13, CAGCTG_AP4_Q5, GOBP_CELL_CELL_SIGNALING, GOCC_COATED_VESICLE, GGGNNTTTCC_NFKB_Q6_01, GOBP_SYNAPTIC_SIGNALING, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON

GO Biological Process (3): vesicle-mediated transport (GO:0016192), synaptic transmission, glutamatergic (GO:0035249), regulation of AMPA receptor activity (GO:2000311)

GO Molecular Function (2): signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (14): endoplasmic reticulum membrane (GO:0005789), ER to Golgi transport vesicle membrane (GO:0012507), postsynaptic density (GO:0014069), dendrite (GO:0030425), AMPA glutamate receptor complex (GO:0032281), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), synapse (GO:0045202), postsynaptic membrane (GO:0045211), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
dendrite	2
postsynapse	2
transport	1
cellular process	1
chemical synaptic transmission	1
AMPA glutamate receptor activity	1
regulation of transmembrane transporter activity	1
regulation of neurotransmitter receptor activity	1
protein binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
COPII-coated ER to Golgi transport vesicle	1
transport vesicle membrane	1
coated vesicle membrane	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
ionotropic glutamate receptor complex	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1
neuron spine	1
cell junction	1
synaptic membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNIH2	CACNG8	Q8WXS5	907
CNIH2	NT5C1A	Q9BXI3	873
CNIH2	GRIA1	P42261	862
CNIH2	SHISA9	B4DS77	826
CNIH2	GRIA3	P42263	823
CNIH2	GRIA2	P42262	784
CNIH2	GSG1L	Q6UXU4	759
CNIH2	SYNDIG1	Q9H7V2	701
CNIH2	CACNG2	Q9Y698	664
CNIH2	GRIA4	P48058	650
CNIH2	DLG4	P78352	639
CNIH2	TGFA	P01135	624
CNIH2	GOLPH3	Q9H4A6	566
CNIH2	GSG1L2	A8MUP6	536
CNIH2	CACNG7	P62955	520

IntAct

19 interactions, top by confidence:

A	B	Type	Score
CNIH2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
TMPRSS2	CNIH2	psi-mi:“MI:0915”(physical association)	0.560
CD53	CNIH2	psi-mi:“MI:0915”(physical association)	0.560
HIBADH	CNIH2	psi-mi:“MI:0915”(physical association)	0.560
CNIH2	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
GORAB	CNIH2	psi-mi:“MI:0915”(physical association)	0.560
CNIH2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.000
CREB3L1	CNIH2	psi-mi:“MI:0915”(physical association)	0.000
CNIH2	TMPRSS2	psi-mi:“MI:0915”(physical association)	0.000
CNIH2	CD53	psi-mi:“MI:0915”(physical association)	0.000
CNIH2	HIBADH	psi-mi:“MI:0915”(physical association)	0.000
CNIH2	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000
CNIH2	GORAB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): CNIH2 (Two-hybrid), CNIH2 (Two-hybrid), CNIH2 (Two-hybrid), CNIH2 (Two-hybrid), CNIH2 (Two-hybrid), TMPRSS2 (Two-hybrid), CNIH2 (Affinity Capture-Western), CNIH2 (Two-hybrid), CNIH2 (Co-crystal Structure), CNIH2 (Co-crystal Structure), CNIH2 (Two-hybrid), CNIH2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3S9V6, A0M8U1, A6NH52, E1BWM5, O35089, P13666, P86050, Q00765, Q0VCK9, Q0X0A5, Q1RLU8, Q29S14, Q2PG42, Q3KNM2, Q3ZC24, Q5BJU5, Q5M7T4, Q5R9I4, Q5R9K4, Q5RE33, Q5T4T1, Q5ZJ41, Q5ZJD7, Q6DD32, Q6GM44, Q6NYF1, Q6P360, Q6PI25, Q7TQ48, Q86TD4, Q8C407, Q8L5Y9, Q8MK44, Q8R1Z9, Q91ZQ0, Q940S0, Q96GC9, Q99K70, Q99KU0, Q9BSR8

Diamond homologs: D0Q0Y7, O35089, O35372, O95406, P49858, P52159, Q0VFK3, Q22361, Q3T126, Q401C0, Q5BIN6, Q5BJU5, Q5BL21, Q5R9M4, Q5RDB5, Q68EY2, Q6P3N5, Q6PI25, Q6ZWS4, Q8TBE1, Q9CX13, Q9P003, P53173, O14038, P38312, Q0DET3, Q3EDD7, Q84W04, Q9P6K6, Q9C7D7, Q2QQ55, Q8GWT5, Q9SZ74

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1477 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66278538:G:GG	donor_gain	1.0000
11:66282323:GGGCA:G	donor_gain	1.0000
11:66282324:GGCA:G	donor_gain	1.0000
11:66282324:GGCAG:G	donor_gain	1.0000
11:66282325:GCA:G	donor_gain	1.0000
11:66282325:GCAG:G	donor_gain	1.0000
11:66282328:G:GG	donor_gain	1.0000
11:66282777:G:GT	donor_gain	1.0000
11:66282777:GAAGG:G	donor_loss	1.0000
11:66282779:AGGT:A	donor_loss	1.0000
11:66282781:GTC:G	donor_loss	1.0000
11:66283031:CCAGC:C	acceptor_loss	1.0000
11:66283032:CAGC:C	acceptor_loss	1.0000
11:66283033:A:AG	acceptor_gain	1.0000
11:66283033:AGC:A	acceptor_loss	1.0000
11:66283033:AGCT:A	acceptor_gain	1.0000
11:66283034:G:GA	acceptor_loss	1.0000
11:66283034:G:GG	acceptor_gain	1.0000
11:66283034:GCTG:G	acceptor_gain	1.0000
11:66283145:G:GT	donor_gain	1.0000
11:66283242:CCCCA:C	acceptor_loss	1.0000
11:66283247:GGT:G	acceptor_gain	1.0000
11:66284867:ACTC:A	donor_loss	1.0000
11:66284869:T:TA	donor_loss	1.0000
11:66284871:A:AC	donor_gain	1.0000
11:66284872:C:CC	donor_gain	1.0000
11:66284872:CA:C	donor_gain	1.0000
11:66284872:CAA:C	donor_gain	1.0000
11:66284872:CAAT:C	donor_gain	1.0000
11:66284872:CAATG:C	donor_gain	1.0000

AlphaMissense

1061 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:66283118:C:A	N94K	0.999
11:66283118:C:G	N94K	0.999
11:66283123:C:G	P96R	0.999
11:66283350:A:C	K138N	0.999
11:66283350:A:T	K138N	0.999
11:66278515:T:C	L20P	0.998
11:66282278:T:C	L34P	0.998
11:66283071:T:C	C79R	0.998
11:66283110:G:C	G92R	0.998
11:66283123:C:A	P96H	0.998
11:66283126:T:A	L97H	0.998
11:66283348:A:G	K138E	0.998
11:66278481:T:C	C9R	0.997
11:66278482:G:A	C9Y	0.997
11:66278483:C:G	C9W	0.997
11:66278497:T:C	L14P	0.997
11:66283134:T:G	Y100D	0.997
11:66283138:A:G	H101R	0.997
11:66283364:T:C	L143P	0.997
11:66283378:T:G	Y148D	0.997
11:66283385:T:C	L150P	0.997
11:66278505:T:C	C17R	0.996
11:66283062:G:C	G76R	0.996
11:66283126:T:G	L97R	0.996
11:66283352:T:C	L139P	0.996
11:66283357:T:C	F141L	0.996
11:66283359:C:A	F141L	0.996
11:66283359:C:G	F141L	0.996
11:66283372:T:C	F146L	0.996
11:66283374:C:A	F146L	0.996

dbSNP variants (sampled 300 via entrez): RS1000735819 (11:66278028 G>A,T), RS1001063872 (11:66279639 C>T), RS1001210720 (11:66278150 G>C,T), RS1001305418 (11:66277729 G>A,T), RS1001397293 (11:66282625 CG>C), RS1001546491 (11:66279350 C>T), RS1002291901 (11:66279988 C>T), RS1003045695 (11:66282617 G>A,C,T), RS1003137009 (11:66283746 G>A,T), RS1003255356 (11:66279696 G>A), RS1003700245 (11:66281213 G>T), RS1004382676 (11:66278927 C>A,G), RS1004434932 (11:66278688 C>A,G,T), RS1004628021 (11:66279281 A>G,T), RS1004659104 (11:66278828 G>C)

Disease associations

OMIM: gene MIM:611288 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07
GCST002773_5	Gout	6.000000e-09
GCST003925_10	Gout	4.000000e-08
GCST008103_21	Bipolar disorder	2.000000e-08
GCST008971_13	Urate levels	9.000000e-06
GCST008972_134	Urate levels	5.000000e-28
GCST010097_12	Insomnia	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases expression, affects expression, increases abundance	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
K 7174	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Aldehydes	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Cannabidiol	decreases expression	1
Cytarabine	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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