CDHR2

Summary

CDHR2 (cadherin related family member 2, HGNC:18231) is a protein-coding gene on chromosome 5q35.2, encoding Cadherin-related family member 2 (Q9BYE9). Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR5 on adjacent microvilli.

This gene is a member of the protocadherin family, which represents a subset of the larger cadherin superfamily. The members of the protocadherin family encode non-classical cadherins that function as calcium-dependent cell-cell adhesion molecules. This protocadherin represents a new candidate for tumor suppression. Alternatively spliced transcript variants that encode the same protein have been identified.

Source: NCBI Gene 54825 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 281 total — 2 pathogenic
• MANE Select transcript: NM_017675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18231
Approved symbol	CDHR2
Name	cadherin related family member 2
Location	5q35.2
Locus type	gene with protein product
Status	Approved
Aliases	PC-LKC, FLJ20124, FLJ20383, PCLKC
Ensembl gene	ENSG00000074276
Ensembl biotype	protein_coding
OMIM	619713
Entrez	54825

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000261944, ENST00000416365, ENST00000506348, ENST00000508085, ENST00000510124, ENST00000510636, ENST00000513031, ENST00000888592, ENST00000888593, ENST00000888594, ENST00000888595, ENST00000888596, ENST00000888597, ENST00000888598, ENST00000888599, ENST00000888600, ENST00000888601, ENST00000955721

RefSeq mRNA: 2 — MANE Select: NM_017675 NM_001171976, NM_017675

CCDS: CCDS34297

Canonical transcript exons

ENST00000261944 — 32 exons

Exon	Start	End
ENSE00000973824	176565672	176565743
ENSE00000973825	176568678	176568817
ENSE00000973826	176568960	176569010
ENSE00000973827	176571213	176571302
ENSE00000973828	176574083	176574172
ENSE00000973840	176584190	176584259
ENSE00000973841	176584410	176585015
ENSE00000973842	176585954	176586025
ENSE00000973843	176586793	176586842
ENSE00001055406	176575724	176575839
ENSE00001055412	176590563	176590687
ENSE00001055414	176575280	176575426
ENSE00001055415	176575084	176575209
ENSE00001055420	176577399	176577554
ENSE00001055423	176581343	176581582
ENSE00001055427	176575506	176575581
ENSE00001129085	176565338	176565404
ENSE00001159367	176578365	176578608
ENSE00001159418	176577637	176577798
ENSE00001196538	176591404	176591484
ENSE00001196573	176578034	176578095
ENSE00001431143	176549342	176549414
ENSE00001507332	176595532	176595824
ENSE00001507333	176592723	176592780
ENSE00001507334	176575952	176576185
ENSE00003470241	176590078	176590146
ENSE00003509115	176590425	176590485
ENSE00003527350	176589330	176589438
ENSE00003528588	176591210	176591323
ENSE00003547257	176589031	176589182
ENSE00003601680	176589528	176589616
ENSE00003649482	176590253	176590330

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 98.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5806 / max 1012.3984, expressed in 47 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60420	1.4149	41
60419	0.1107	27
60425	0.0459	3
60423	0.0062	3
60424	0.0029	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.99	gold quality
ileal mucosa	UBERON:0000331	97.16	gold quality
duodenum	UBERON:0002114	96.99	gold quality
mucosa of transverse colon	UBERON:0004991	92.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.49	gold quality
small intestine	UBERON:0002108	91.04	gold quality
cortical plate	UBERON:0005343	89.43	gold quality
rectum	UBERON:0001052	88.84	gold quality
left testis	UBERON:0004533	88.00	gold quality
right lobe of liver	UBERON:0001114	87.48	gold quality
sperm	CL:0000019	86.73	gold quality
jejunum	UBERON:0002115	86.39	gold quality
colonic mucosa	UBERON:0000317	86.38	gold quality
liver	UBERON:0002107	86.31	gold quality
right testis	UBERON:0004534	86.27	gold quality
transverse colon	UBERON:0001157	85.38	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.64	gold quality
male germ cell	CL:0000015	84.44	gold quality
testis	UBERON:0000473	84.29	gold quality
right frontal lobe	UBERON:0002810	83.40	gold quality
anterior cingulate cortex	UBERON:0009835	83.35	gold quality
cingulate cortex	UBERON:0003027	83.21	gold quality
ganglionic eminence	UBERON:0004023	82.17	gold quality
amygdala	UBERON:0001876	81.71	gold quality
pancreatic ductal cell	CL:0002079	81.68	silver quality
adult mammalian kidney	UBERON:0000082	81.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.60	gold quality
islet of Langerhans	UBERON:0000006	81.28	gold quality
cerebellar hemisphere	UBERON:0002245	80.78	gold quality
cerebellar cortex	UBERON:0002129	80.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	67.64
E-ANND-3	yes	11.23

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• suppression of beta-catenin signaling by PCDH24 leads to contact inhibition (PMID:19383367)
• CDHR24 is directly involved in cell and tissue morphogenesis (PMID:22628312)
• Study found that brush border assembly is driven by the formation of Ca(2+)-dependent adhesion links between adjacent microvilli. Intermicrovillar links are composed of protocadherin-24 and mucin-like protocadherin, which target to microvillar tips and interact to form a trans-heterophilic complex. (PMID:24725409)
• Heterophilic and homophilic cadherin interactions in intestinal intermicrovillar links are species dependent. (PMID:34871294)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdhr2	ENSMUSG00000034918
rattus_norvegicus	Cdhr2	ENSRNOG00000017917

Paralogs (33): CDH1 (ENSG00000039068), CDH10 (ENSG00000040731), CDH3 (ENSG00000062038), CDH19 (ENSG00000071991), CDH17 (ENSG00000079112), CDH7 (ENSG00000081138), PCDH11Y (ENSG00000099715), CDHR5 (ENSG00000099834), CDH20 (ENSG00000101542), PCDH11X (ENSG00000102290), CDH23 (ENSG00000107736), CDH9 (ENSG00000113100), CDH6 (ENSG00000113361), CDH26 (ENSG00000124215), CDHR3 (ENSG00000128536), CDH15 (ENSG00000129910), CDH24 (ENSG00000139880), CDH11 (ENSG00000140937), CDH13 (ENSG00000140945), CDH18 (ENSG00000145526), CDHR1 (ENSG00000148600), CDH22 (ENSG00000149654), CDH8 (ENSG00000150394), CDH12 (ENSG00000154162), PCDH1 (ENSG00000156453), DCHS1 (ENSG00000166341), PCDH7 (ENSG00000169851), CDH2 (ENSG00000170558), CDH4 (ENSG00000179242), CDH5 (ENSG00000179776), PCDH9 (ENSG00000184226), DCHS2 (ENSG00000197410), PCDH20 (ENSG00000280165)

Protein

Protein identifiers

Cadherin-related family member 2 — Q9BYE9 (reviewed: Q9BYE9)

Alternative names: Protocadherin LKC, Protocadherin-24

All UniProt accessions (2): Q9BYE9, D6REJ3

UniProt curated annotations — full annotation on UniProt →

Function. Intermicrovillar adhesion molecule that forms, via its extracellular domain, calcium-dependent heterophilic complexes with CDHR5 on adjacent microvilli. Thereby, controls the packing of microvilli at the apical membrane of epithelial cells. Through its cytoplasmic domain, interacts with microvillus cytoplasmic proteins to form the intermicrovillar adhesion complex/IMAC. This complex plays a central role in microvilli and epithelial brush border differentiation. May also play a role in cell-cell adhesion and contact inhibition in epithelial cells.

Subunit / interactions. Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5. Interacts with MAST2. Interacts (via cytoplasmic domain) with USH1C and MYO7B; required for proper localization of CDHR2 to microvilli tips and its function in brush border differentiation.

Subcellular location. Apical cell membrane. Cell projection. Microvillus membrane. Cell junction.

Tissue specificity. Highly expressed in liver, kidney and colon. Moderately expressed in small intestine. Down-regulated in a number of liver and colon cancers. Expressed in duodenum with higher expression in enterocytes along the villus axis and lower expression in crypts (at protein level).

Domain organisation. The cadherin 1 domain is required for binding to CDHR5.

RefSeq proteins (2): NP_001165447, NP_060145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002126	Cadherin-like_dom	Domain
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site

Pfam: PF00028

UniProt features (81 total): glycosylation site 24, strand 18, domain 9, sequence variant 9, helix 4, turn 3, region of interest 2, compositionally biased region 2, modified residue 2, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5CZR	X-RAY DIFFRACTION	2.3
7N86	X-RAY DIFFRACTION	3.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYE9-F1	80.84	0.31

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 (2): 1248, 1299

Glycosylation sites (24): 29, 134, 182, 188, 195, 300, 355, 371, 401, 460, 565, 600, 616, 632, 680, 696, 701, 775, 821, 871 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
1310	loss of interaction with ush1c.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 93 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MODULE_205, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_DETECTION_OF_STIMULUS, GOBP_REGULATION_OF_MICROVILLUS_ORGANIZATION, GOBP_HOMOTYPIC_CELL_CELL_ADHESION, GOBP_CELL_PROJECTION_ORGANIZATION, BREDEMEYER_RAG_SIGNALING_NOT_VIA_ATM_UP

GO Biological Process (12): homophilic cell-cell adhesion (GO:0007156), axonogenesis (GO:0007409), epithelial cell differentiation (GO:0030855), regulation of microvillus length (GO:0032532), cell-cell adhesion mediated by cadherin (GO:0044331), negative regulation of cell growth involved in contact inhibition (GO:0060243), intermicrovillar adhesion (GO:0090675), brush border assembly (GO:1904970), cell adhesion (GO:0007155), cell differentiation (GO:0030154), epithelium development (GO:0060429), cell-cell adhesion (GO:0098609)

GO Molecular Function (3): calcium ion binding (GO:0005509), cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), microvillus (GO:0005902), brush border (GO:0005903), adherens junction (GO:0005912), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), microvillus membrane (GO:0031528), extracellular exosome (GO:0070062), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	2
microvillus	2
apical part of cell	2
cell projection membrane	2
cellular anatomical structure	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
cell differentiation	1
epithelium development	1
regulation of microvillus organization	1
regulation of cell projection size	1
negative regulation of cell growth	1
contact inhibition	1
homotypic cell-cell adhesion	1
brush border assembly	1
cellular component assembly	1
cellular process	1
cellular developmental process	1
tissue development	1
cell adhesion	1
metal ion binding	1
protein binding	1
binding	1
membrane	1
cell periphery	1
actin filament bundle	1
actin-based cell projection	1
cluster of actin-based cell projections	1
cell-cell junction	1
plasma membrane region	1
brush border	1
apical plasma membrane	1
extracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

894 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDHR2	CDHR5	Q9HBB8	991
CDHR2	E9PNW1	E9PNW1	828
CDHR2	ANKS4B	Q8N8V4	790
CDHR2	MYO7B	Q6PIF6	790
CDHR2	GPRIN1	Q7Z2K8	566
CDHR2	KNDC1	Q76NI1	518
CDHR2	ADGRA1	Q86SQ6	476
CDHR2	ESPN	B1AK53	463
CDHR2	IGDCC4	Q8TDY8	433
CDHR2	CDHR4	A6H8M9	432
CDHR2	PCDH15	Q96QU1	420
CDHR2	ACRV1	P26436	417
CDHR2	OR8A1	Q8NGG7	410
CDHR2	RAB24	Q969Q5	398
CDHR2	TMEM164	Q5U3C3	391

IntAct

22 interactions, top by confidence:

A	B	Type	Score
CDHR2	CDHR5	psi-mi:“MI:0407”(direct interaction)	0.590
CDHR5	CDHR2	psi-mi:“MI:0407”(direct interaction)	0.590
CDHR5	CDHR2	psi-mi:“MI:0915”(physical association)	0.590
CDHR2	CDHR5	psi-mi:“MI:0915”(physical association)	0.590
CDHR2	MAST2	psi-mi:“MI:0915”(physical association)	0.540
MAST2	CDHR2	psi-mi:“MI:0915”(physical association)	0.540
MAST2	CDHR2	psi-mi:“MI:0403”(colocalization)	0.540
CDHR2	USH1C	psi-mi:“MI:0915”(physical association)	0.520
USH1C	CDHR2	psi-mi:“MI:0915”(physical association)	0.520
CDHR2	MYO7B	psi-mi:“MI:0915”(physical association)	0.460
CDHR2	MYO7B	psi-mi:“MI:0403”(colocalization)	0.460
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
RPS6KA2	IPO7	psi-mi:“MI:0914”(association)	0.350
RPS6KA6	HMGN1	psi-mi:“MI:0914”(association)	0.350
CDHR2	HIP1R	psi-mi:“MI:0914”(association)	0.350
CDHR2	CDHR5	psi-mi:“MI:0403”(colocalization)	0.270
CDHR2	USH1C	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (15): MAST2 (Affinity Capture-Western), MAST2 (Co-localization), NF1 (Affinity Capture-MS), HIP1R (Affinity Capture-MS), MAST2 (Two-hybrid), MRS2 (Affinity Capture-MS), LAMB1 (Affinity Capture-MS), TMTC2 (Affinity Capture-MS), SURF1 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), TBCD (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), CDHR2 (Affinity Capture-MS), CDHR2 (Affinity Capture-MS), NUP88 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: E9Q7P9, O88277, O93319, P55280, P55281, P55285, P55289, P70408, P79995, P97326, Q08DJ5, Q12864, Q13634, Q14517, Q24298, Q2PZL6, Q3SWX5, Q5DWV1, Q5DWV2, Q5F226, Q63315, Q6B3P0, Q6KEQ9, Q6V0I7, Q6WXV7, Q6WYY1, Q6X862, Q6ZTQ4, Q71M42, Q8BIZ0, Q8BL00, Q8BM92, Q8BNA6, Q8N6Y1, Q8QGH3, Q8R508, Q8TDW7, Q90762, Q90763, Q91838

Diamond homologs: B2KI42, E9Q7P9, O18926, O54800, O55075, O93319, P08641, P20310, P30944, P33147, P55280, P55284, P55286, P55287, P55288, P58365, P97291, P97326, Q2PZL6, Q3SWX5, Q63418, Q6B457, Q6PB90, Q6PFX6, Q767I8, Q86UP0, Q8AYD0, Q8UVJ7, Q8VHP6, Q8WN91, Q90762, Q90Z37, Q91XU7, Q91XZ4, Q96JP9, Q99PF4, Q9BYE9, Q9H251, Q9QYP2, D4ACX8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	228
Likely benign	26
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1707460	Single allele	Pathogenic
2579264	GRCh38/hg38 5q35.2-35.3(chr5:176447531-177312407)x1	Pathogenic

SpliceAI

5205 predictions. Top by Δscore:

Variant	Effect	Δscore
5:176542770:G:GG	donor_gain	1.0000
5:176568813:ACGAG:A	donor_loss	1.0000
5:176568814:CGAGG:C	donor_loss	1.0000
5:176568815:GAGGT:G	donor_loss	1.0000
5:176568816:AGG:A	donor_loss	1.0000
5:176568817:GGTA:G	donor_loss	1.0000
5:176568818:G:GA	donor_loss	1.0000
5:176568819:T:G	donor_loss	1.0000
5:176568948:T:TA	acceptor_gain	1.0000
5:176571298:ACGAG:A	donor_loss	1.0000
5:176571300:GAGGT:G	donor_loss	1.0000
5:176571301:AGGTG:A	donor_loss	1.0000
5:176571302:GGTG:G	donor_loss	1.0000
5:176571303:G:A	donor_loss	1.0000
5:176571322:G:GA	donor_gain	1.0000
5:176574080:CAGAC:C	acceptor_loss	1.0000
5:176574081:A:C	acceptor_loss	1.0000
5:176574082:GACC:G	acceptor_gain	1.0000
5:176574169:GAAG:G	donor_gain	1.0000
5:176574171:AGG:A	donor_loss	1.0000
5:176574173:G:GC	donor_loss	1.0000
5:176574174:T:A	donor_loss	1.0000
5:176575082:A:AG	acceptor_gain	1.0000
5:176575083:G:GG	acceptor_gain	1.0000
5:176575083:GGTC:G	acceptor_gain	1.0000
5:176575210:G:GG	donor_gain	1.0000
5:176575387:G:GT	donor_gain	1.0000
5:176575415:G:GT	donor_gain	1.0000
5:176575422:CCAAG:C	donor_loss	1.0000
5:176575423:CAAG:C	donor_loss	1.0000

AlphaMissense

8585 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:176577451:T:C	F416S	0.993
5:176576049:T:C	F353S	0.992
5:176577644:C:A	A453D	0.991
5:176584190:G:C	D687H	0.991
5:176576043:C:A	P351H	0.990
5:176578376:T:C	F529S	0.990
5:176578505:T:C	L572P	0.990
5:176589380:T:A	V1020D	0.990
5:176589568:T:G	F1053C	0.990
5:176576048:T:C	F353L	0.989
5:176576050:T:A	F353L	0.989
5:176576050:T:G	F353L	0.989
5:176577450:T:C	F416L	0.989
5:176577452:C:A	F416L	0.989
5:176577452:C:G	F416L	0.989
5:176589567:T:C	F1053L	0.989
5:176589569:C:A	F1053L	0.989
5:176589569:C:G	F1053L	0.989
5:176571262:C:A	P122H	0.988
5:176571268:T:G	F124C	0.988
5:176574131:G:C	D152H	0.988
5:176575953:C:A	A321D	0.988
5:176577719:C:A	P478H	0.988
5:176578468:G:C	A560P	0.988
5:176584439:G:C	D720H	0.988
5:176584476:T:C	F732S	0.988
5:176589367:T:G	Y1016D	0.988
5:176584440:A:C	D720A	0.987
5:176589568:T:C	F1053S	0.987
5:176574132:A:C	D152A	0.986

dbSNP variants (sampled 300 via entrez): RS1000015036 (5:176588750 G>T), RS1000078586 (5:176552825 C>T), RS1000216487 (5:176575084 G>A), RS1000218139 (5:176574451 A>C), RS1000231844 (5:176548112 C>G,T), RS1000302468 (5:176557914 G>T), RS1000334272 (5:176563413 C>A), RS1000428310 (5:176591108 C>T), RS1000446015 (5:176569086 C>A,T), RS1000539911 (5:176549436 G>A), RS1000577895 (5:176563717 C>T), RS1000586514 (5:176596461 A>G), RS1000724603 (5:176579759 C>T), RS1000732135 (5:176580446 T>C), RS1000786103 (5:176595383 G>A)

Disease associations

OMIM: gene MIM:619713 | disease phenotypes: MIM:117550

GenCC curated gene-disease

Mondo (2): 5q35 microduplication syndrome (MONDO:0016461), Sotos syndrome (MONDO:0019349)

Orphanet (2): 5q35 microduplication syndrome (Orphanet:228415), Sotos syndrome (Orphanet:821)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008163_438	Height	3.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D058495	Sotos Syndrome	C16.131.077.889; C16.131.260.905; C16.320.180.905

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	2
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Niclosamide	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development