CLRN2

Summary

CLRN2 (clarin 2, HGNC:33939) is a protein-coding gene on chromosome 4p15.32, encoding Clarin-2 (A0PK11). Plays a key role to hearing function.

This gene belongs to the clarin family of genes. The clarins appear to belong to a large superfamily of small integral membrane glycoproteins with four transmembrane domains. The exact function of this gene is unknown.

Source: NCBI Gene 645104 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 50 total — 1 pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_001079827

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33939
Approved symbol	CLRN2
Name	clarin 2
Location	4p15.32
Locus type	gene with protein product
Status	Approved
Aliases	DFNB117
Ensembl gene	ENSG00000249581
Ensembl biotype	protein_coding
OMIM	618988
Entrez	645104

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000511148

RefSeq mRNA: 1 — MANE Select: NM_001079827 NM_001079827

CCDS: CCDS47032

Canonical transcript exons

ENST00000511148 — 3 exons

Exon	Start	End
ENSE00002226254	17526817	17527104
ENSE00002234066	17515165	17515519
ENSE00002298073	17522864	17523043

Expression profiles

Bgee: expression breadth broad, 12 present calls, max score 47.28.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	47.28	gold quality
granulocyte	CL:0000094	41.72	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
prefrontal cortex	UBERON:0000451	34.52	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
bone marrow	UBERON:0002371	33.09	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
frontal cortex	UBERON:0001870	30.81	silver quality
right hemisphere of cerebellum	UBERON:0014890	30.22	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
cerebral cortex	UBERON:0000956	29.74	gold quality
brain	UBERON:0000955	29.19	silver quality
leukocyte	CL:0000738	28.47	gold quality
duodenum	UBERON:0002114	28.14	gold quality
Ammon’s horn	UBERON:0001954	27.77	silver quality
monocyte	CL:0000576	27.75	gold quality
lymph node	UBERON:0000029	27.57	gold quality
superior frontal gyrus	UBERON:0002661	27.24	gold quality
tonsil	UBERON:0002372	27.05	gold quality
kidney	UBERON:0002113	26.76	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
adult mammalian kidney	UBERON:0000082	26.21	gold quality
blood	UBERON:0000178	26.14	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
cortex of kidney	UBERON:0001225	25.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.30

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. (PMID:31448880)
• A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans. (PMID:33496845)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clrn2	ENSDARG00000070321
mus_musculus	Clrn2	ENSMUSG00000049530
rattus_norvegicus	Clrn2	ENSRNOG00000027195
drosophila_melanogaster	CG1103	FBGN0037235
caenorhabditis_elegans		WBGENE00235279

Paralogs (2): CLRN1 (ENSG00000163646), CLRN3 (ENSG00000180745)

Protein

Protein identifiers

Clarin-2 — A0PK11 (reviewed: A0PK11)

All UniProt accessions (1): A0PK11

UniProt curated annotations — full annotation on UniProt →

Function. Plays a key role to hearing function. Required for normal organization and maintenance of the stereocilia bundle and for mechano-electrical transduction.

Subcellular location. Cell projection. Stereocilium membrane.

Disease relevance. Deafness, autosomal recessive, 117 (DFNB117) [MIM:619174] A form of non-syndromic deafness characterized by prelingual, moderate-to-profound sensorineural hearing loss. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the clarin family.

RefSeq proteins (1): NP_001073296* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026748	Clarin	Family

Pfam: PF25807

UniProt features (9 total): transmembrane region 4, sequence variant 3, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0PK11-F1	91.15	0.80

Functional residue map

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

Glycosylation sites (1): 48

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 48 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_EAR_MORPHOGENESIS, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_AUDITORY_RECEPTOR_CELL_DEVELOPMENT, GOBP_MECHANORECEPTOR_DIFFERENTIATION, GOBP_HAIR_CELL_DIFFERENTIATION, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION

GO Biological Process (4): sensory perception of sound (GO:0007605), auditory receptor cell stereocilium organization (GO:0060088), stereocilium maintenance (GO:0120045), inner ear auditory receptor cell differentiation (GO:0042491)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): stereocilium bundle (GO:0032421), stereocilium membrane (GO:0060171), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inner ear receptor cell stereocilium organization	2
stereocilium	2
cellular anatomical structure	2
sensory perception of mechanical stimulus	1
auditory receptor cell morphogenesis	1
cellular component maintenance	1
hair cell differentiation	1
inner ear receptor cell differentiation	1
binding	1
cluster of actin-based cell projections	1
neuron projection membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

554 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLRN2	CACNG2	Q9Y698	723
CLRN2	GRXCR2	A6NFK2	565
CLRN2	E9PNW1	E9PNW1	555
CLRN2	STRC	Q7RTU9	543
CLRN2	CEP295NL	Q96MC4	531
CLRN2	TMC1	Q8TDI8	505
CLRN2	PPP1R17	O96001	504
CLRN2	KLHDC7B	Q96G42	490
CLRN2	CHRNA10	Q9GZZ6	480
CLRN2	CHRNA9	Q9UGM1	458
CLRN2	PCDH15	Q96QU1	449
CLRN2	WHRN	Q9P202	420
CLRN2	LRRC31	Q6UY01	417
CLRN2	TCAP	O15273	413
CLRN2	CEP295	Q9C0D2	411

IntAct

39 interactions, top by confidence:

A	B	Type	Score
CLRN2	KLRC1	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	STOM	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	CLEC2D	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	VSIR	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	CLDN5	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	SIT1	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	NEMP1	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	TEX29	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	LRRC25	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	ARL6IP6	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	FAM234B	psi-mi:“MI:0914”(association)	0.350
CLRN2	CA12	psi-mi:“MI:0914”(association)	0.350
CLRN2	ARL6IP6	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	KLRC1	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	STOM	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	CLEC2D	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	FNDC9	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	CLDN5	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	SIT1	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	NEMP1	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	TEX29	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	SSMEM1	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	VSIR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (75): CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), CLRN2 (Two-hybrid), KIAA1467 (Affinity Capture-MS), MBOAT7 (Affinity Capture-MS), SLC30A1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8RY99, A0PK11, A9UL59, B2RVW2, B4L184, B4LC58, B4N5D3, D3ZFW5, O95473, P23290, P35801, P35802, P35803, P36964, P36965, P51674, P56749, P58418, P79826, Q0IIL2, Q0P4G7, Q0VD07, Q11085, Q13491, Q2YDD6, Q53R12, Q5R603, Q5R9K1, Q5R9Q3, Q5R9R3, Q5T9L3, Q5ZLR1, Q6AYR5, Q6CRM6, Q6DID7, Q6P689, Q6UX40, Q754N9, Q7YWX7, Q812E9

Diamond homologs: A0A2R8RY99, A0PK11, B2RVW2, P58418, Q8CJ58, Q8K445

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	41
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
996040	NM_001079827.2(CLRN2):c.494C>A (p.Thr165Lys)	Pathogenic

SpliceAI

394 predictions. Top by Δscore:

Variant	Effect	Δscore
4:17515471:TGTA:T	donor_gain	1.0000
4:17522862:A:AG	acceptor_gain	1.0000
4:17522863:G:GA	acceptor_gain	1.0000
4:17515430:TC:T	donor_gain	0.9900
4:17515472:GTAA:G	donor_gain	0.9900
4:17515518:GA:G	donor_gain	0.9900
4:17515520:G:GG	donor_gain	0.9900
4:17522863:GT:G	acceptor_gain	0.9900
4:17522863:GTC:G	acceptor_gain	0.9900
4:17522863:GTCT:G	acceptor_gain	0.9900
4:17522863:GTCTT:G	acceptor_gain	0.9900
4:17523041:CAGGT:C	donor_loss	0.9900
4:17523042:AGGTA:A	donor_loss	0.9900
4:17523043:GGTAA:G	donor_loss	0.9900
4:17523044:G:C	donor_loss	0.9900
4:17523045:T:TC	donor_loss	0.9900
4:17524640:A:AG	donor_gain	0.9900
4:17515352:T:TA	donor_gain	0.9800
4:17515353:A:AA	donor_gain	0.9800
4:17515517:CGA:C	donor_gain	0.9800
4:17515518:GAG:G	donor_gain	0.9800
4:17515518:GAGTG:G	donor_loss	0.9800
4:17515519:AGTG:A	donor_loss	0.9800
4:17515520:G:A	donor_loss	0.9800
4:17515521:TGA:T	donor_loss	0.9800
4:17515522:G:GT	donor_loss	0.9800
4:17515523:AGTAT:A	donor_loss	0.9800
4:17522861:CA:C	acceptor_loss	0.9800
4:17522862:A:G	acceptor_loss	0.9800
4:17524640:A:G	donor_gain	0.9800

AlphaMissense

1504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:17515435:T:C	F57L	0.995
4:17515437:C:A	F57L	0.995
4:17515437:C:G	F57L	0.995
4:17526966:A:C	S195R	0.994
4:17526968:C:A	S195R	0.994
4:17526968:C:G	S195R	0.994
4:17515315:A:C	S17R	0.986
4:17515317:C:A	S17R	0.986
4:17515317:C:G	S17R	0.986
4:17515384:T:A	C40S	0.984
4:17515385:G:C	C40S	0.984
4:17522953:A:C	S115R	0.983
4:17522955:C:A	S115R	0.983
4:17522955:C:G	S115R	0.983
4:17515436:T:C	F57S	0.982
4:17515486:T:A	C74S	0.982
4:17515487:G:C	C74S	0.982
4:17515386:T:G	C40W	0.981
4:17515384:T:C	C40R	0.979
4:17515486:T:C	C74R	0.976
4:17515385:G:A	C40Y	0.975
4:17515436:T:G	F57C	0.975
4:17515457:G:A	G64E	0.972
4:17523033:T:A	N141K	0.972
4:17523033:T:G	N141K	0.972
4:17515441:G:T	G59W	0.971
4:17515363:T:A	W33R	0.968
4:17515363:T:C	W33R	0.968
4:17515469:G:A	G68E	0.967
4:17515468:G:A	G68R	0.965

dbSNP variants (sampled 300 via entrez): RS1000083393 (4:17521540 C>G,T), RS1000130838 (4:17513869 C>G), RS1000358056 (4:17527341 A>G), RS1000493695 (4:17515818 T>C), RS1000784977 (4:17521778 A>T), RS1000837052 (4:17520145 T>C), RS1000855665 (4:17520320 CTTTT>C), RS1001071805 (4:17521303 T>C), RS1001081658 (4:17525827 T>C), RS1001099755 (4:17520379 T>C), RS1001383798 (4:17520879 A>G), RS1001417312 (4:17514157 G>A), RS1001573065 (4:17527439 T>C), RS1001619312 (4:17514703 C>G,T), RS1001944217 (4:17514926 A>G)

Disease associations

OMIM: gene MIM:618988 | disease phenotypes: MIM:619174

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	Autosomal recessive
hearing loss, autosomal recessive 117	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AR

Mondo (2): hearing loss, autosomal recessive 117 (MONDO:0030905), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001751	Abnormal vestibular function
HP:0011463	Childhood onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_53	Metabolite levels	5.000000e-06
GCST012442_32	Age-related hearing impairment	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010474	cystathionine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
Benzo(a)pyrene	decreases methylation	1
Methapyrilene	increases methylation	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations