NRCAM

Summary

NRCAM (neuronal cell adhesion molecule, HGNC:7994) is a protein-coding gene on chromosome 7q31.1, encoding Neuronal cell adhesion molecule (Q92823). Cell adhesion protein that is required for normal responses to cell-cell contacts in brain and in the peripheral nervous system.

Cell adhesion molecules (CAMs) are members of the immunoglobulin superfamily. This gene encodes a neuronal cell adhesion molecule with multiple immunoglobulin-like C2-type domains and fibronectin type-III domains. This ankyrin-binding protein is involved in neuron-neuron adhesion and promotes directional signaling during axonal cone growth. This gene is also expressed in non-neural tissues and may play a general role in cell-cell communication via signaling from its intracellular domain to the actin cytoskeleton during directional cell migration. Allelic variants of this gene have been associated with autism and addiction vulnerability. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 4897 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with neuromuscular and skeletal abnormalities (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 261 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 62
• MANE Select transcript: NM_001037132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7994
Approved symbol	NRCAM
Name	neuronal cell adhesion molecule
Location	7q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0343, Bravo
Ensembl gene	ENSG00000091129
Ensembl biotype	protein_coding
OMIM	601581
Entrez	4897

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 28 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000351718, ENST00000379024, ENST00000379028, ENST00000413765, ENST00000415105, ENST00000417701, ENST00000418239, ENST00000419936, ENST00000442580, ENST00000445634, ENST00000456431, ENST00000465585, ENST00000489800, ENST00000522550, ENST00000878868, ENST00000878869, ENST00000878870, ENST00000878871, ENST00000878872, ENST00000878874, ENST00000878875, ENST00000878876, ENST00000932236, ENST00000953262, ENST00000953263, ENST00000953264, ENST00000953265, ENST00000953266, ENST00000953267, ENST00000953268, ENST00000953269, ENST00000953270

RefSeq mRNA: 67 — MANE Select: NM_001037132 NM_001037132, NM_001193582, NM_001193583, NM_001193584, NM_001371119, NM_001371122, NM_001371123, NM_001371124, NM_001371125, NM_001371126, NM_001371127, NM_001371128, NM_001371129, NM_001371130, NM_001371131, NM_001371132, NM_001371133, NM_001371134, NM_001371135, NM_001371136, NM_001371137, NM_001371138, NM_001371139, NM_001371140, NM_001371141, NM_001371142, NM_001371143, NM_001371144, NM_001371145, NM_001371146, NM_001371147, NM_001371148, NM_001371149, NM_001371150, NM_001371151, NM_001371152, NM_001371153, NM_001371154, NM_001371155, NM_001371156, NM_001371157, NM_001371158, NM_001371159, NM_001371160, NM_001371161, NM_001371162, NM_001371163, NM_001371164, NM_001371165, NM_001371166, NM_001371167, NM_001371168, NM_001371169, NM_001371170, NM_001371171, NM_001371172, NM_001371173, NM_001371174, NM_001371175, NM_001371176, NM_001371177, NM_001371178, NM_001371179, NM_001371180, NM_001371181, NM_001371182, NM_005010

CCDS: CCDS47686, CCDS55153, CCDS5751, CCDS75652

Canonical transcript exons

ENST00000379028 — 33 exons

Exon	Start	End
ENSE00000716769	108182695	108182920
ENSE00000716772	108189645	108189746
ENSE00000716774	108194024	108194171
ENSE00000716775	108194262	108194428
ENSE00000881794	108177990	108178112
ENSE00000881795	108180223	108180427
ENSE00000881796	108181822	108181937
ENSE00000881798	108184241	108184311
ENSE00000881799	108184417	108184614
ENSE00000881802	108191729	108191853
ENSE00000881805	108195761	108195872
ENSE00000881807	108197956	108198099
ENSE00000881808	108207528	108207659
ENSE00000881810	108209421	108209605
ENSE00000881813	108223725	108223836
ENSE00000881814	108225645	108225701
ENSE00000881815	108226208	108226378
ENSE00000881818	108231031	108231153
ENSE00000881820	108232326	108232522
ENSE00000881822	108234583	108234688
ENSE00001352863	108239959	108240170
ENSE00001352869	108312665	108312731
ENSE00001352872	108399436	108399593
ENSE00001479549	108166921	108167073
ENSE00001479555	108175322	108175357
ENSE00001479582	108191254	108191283
ENSE00001665448	108168277	108168402
ENSE00002440365	108237752	108237769
ENSE00003568189	108160361	108160492
ENSE00003596395	108159463	108159541
ENSE00003623698	108176430	108176606
ENSE00003850294	108147649	108150147
ENSE00003896362	108456243	108456436

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4849 / max 411.0780, expressed in 1004 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85682	12.3819	967
85680	1.6165	425
85681	0.7009	267
85685	0.6059	162
85676	0.5623	165
85683	0.4222	167
85673	0.2175	33
85675	0.1911	70
85684	0.1668	58
85677	0.1210	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.41	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.34	gold quality
middle temporal gyrus	UBERON:0002771	99.17	gold quality
primary visual cortex	UBERON:0002436	98.68	gold quality
cortical plate	UBERON:0005343	98.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.50	gold quality
occipital lobe	UBERON:0002021	98.41	gold quality
adrenal tissue	UBERON:0018303	98.36	gold quality
prefrontal cortex	UBERON:0000451	98.34	gold quality
superior frontal gyrus	UBERON:0002661	98.29	gold quality
entorhinal cortex	UBERON:0002728	98.27	gold quality
right frontal lobe	UBERON:0002810	98.24	gold quality
temporal lobe	UBERON:0001871	98.19	gold quality
amygdala	UBERON:0001876	98.18	gold quality
cerebral cortex	UBERON:0000956	98.02	gold quality
frontal cortex	UBERON:0001870	97.99	gold quality
pons	UBERON:0000988	97.89	gold quality
neocortex	UBERON:0001950	97.88	gold quality
endothelial cell	CL:0000115	97.85	gold quality
parietal lobe	UBERON:0001872	97.85	gold quality
postcentral gyrus	UBERON:0002581	97.81	gold quality
Ammon’s horn	UBERON:0001954	97.74	gold quality
telencephalon	UBERON:0001893	97.73	gold quality
CA1 field of hippocampus	UBERON:0003881	97.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.63	gold quality
cingulate cortex	UBERON:0003027	97.59	gold quality
anterior cingulate cortex	UBERON:0009835	97.53	gold quality
substantia nigra pars compacta	UBERON:0001965	97.52	gold quality
forebrain	UBERON:0001890	97.50	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	76.16
E-CURD-119	yes	36.78
E-GEOD-84465	yes	25.69
E-HCAD-25	yes	24.06
E-ANND-3	yes	11.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, GATA3, HNF4A, LEF1

miRNA regulators (miRDB)

152 targeting NRCAM, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 18)

• Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM (PMID:11866539)
• induction of Nr-CAM transcription plays a role in melanoma and colon cancer tumorigenesis (PMID:12183361)
• NrCAM is overexpressed in human papillary thyroid carcinoma at the mRNA and protein levels, whatever the tumour stage. (PMID:17667921)
• Distinct cytokeratin 7, cytokeratin 19, & neuronal cell adhesion molecule staining patterns are seen in hepatic adenoma & focal nodular hyperplasia possibly suggest activation of different subsets of hepatic progenitor/stem cell. (PMID:18602664)
• our results indicated that the NRCAM gene is one of the strong candidate genes for autism (PMID:18664314)
• Nr-CAM protein expression is upregulated in colorectal cancer tissues; Nr-CAM overexpression is an independent marker of poor prognosis among advanced CRC patients, and a possible predictive marker for non-beneficence to 5-fluorouracil-based chemotherapy (PMID:21718388)
• Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM (PMID:21876539)
• mechanisms of NrCAM participation in development and how these might be perturbed in disorders are reviewed. [review] (PMID:22182708)
• A high level of Nr-CAM expression is associated with favorable tumor phenotype and reduced risk of prostate cancer recurrence. (PMID:23338556)
• Increased gene expression of NrCAM may be used as a potential diagnostic marker for papillary thyroid cancer. (PMID:27732334)
• Coffee consumption is causally associated with an increased risk of osteoarthritis. SNPs in NCALD, POR, CYP1A1 and NRCAM were identified. (PMID:30076541)
• High NRCAM expression is associated with prostate cancer progression. (PMID:31322225)
• Recent insights into the role of L1CAM in cancer initiation and progression. (PMID:32588424)
• LncRNA RUNX1-IT1 affects the differentiation of Th1 cells by regulating NrCAM transcription in Graves’ disease. (PMID:35220890)
• NRCAM acts as a prognostic biomarker and promotes the tumor progression in gastric cancer via EMT pathway. (PMID:35763884)
• Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype. (PMID:36181733)
• Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma. (PMID:37993901)
• CircNRCAM up-regulates NRCAM to promote papillary thyroid carcinoma progression. (PMID:38485895)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrcama	ENSDARG00000006396
mus_musculus	Nrcam	ENSMUSG00000020598
rattus_norvegicus	Nrcam	ENSRNOG00000004067

Paralogs (36): CNTN1 (ENSG00000018236), CDON (ENSG00000064309), NEO1 (ENSG00000067141), SDK2 (ENSG00000069188), IGSF9B (ENSG00000080854), IGSF9 (ENSG00000085552), MXRA5 (ENSG00000101825), IGDCC4 (ENSG00000103742), CNTN3 (ENSG00000113805), IGSF21 (ENSG00000117154), CNTN6 (ENSG00000134115), CHL1 (ENSG00000134121), PTPRQ (ENSG00000139304), CNTN4 (ENSG00000144619), BOC (ENSG00000144857), SDK1 (ENSG00000146555), HMCN2 (ENSG00000148357), NCAM1 (ENSG00000149294), CNTN5 (ENSG00000149972), IGSF10 (ENSG00000152580), ROBO4 (ENSG00000154133), ROBO3 (ENSG00000154134), NCAM2 (ENSG00000154654), VCAM1 (ENSG00000162692), NFASC (ENSG00000163531), PRTG (ENSG00000166450), ROBO1 (ENSG00000169855), DSCAM (ENSG00000171587), IGDCC3 (ENSG00000174498), VSIG10 (ENSG00000176834), DSCAML1 (ENSG00000177103), CNTN2 (ENSG00000184144), ROBO2 (ENSG00000185008), VSIG10L (ENSG00000186806), DCC (ENSG00000187323), L1CAM (ENSG00000198910)

Protein

Protein identifiers

Neuronal cell adhesion molecule — Q92823 (reviewed: Q92823)

Alternative names: Neuronal surface protein Bravo, NgCAM-related cell adhesion molecule

All UniProt accessions (8): Q92823, A0A1S5UZH4, C9J8B6, C9JF43, C9JH43, C9JUR7, C9JYY6, H7C132

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion protein that is required for normal responses to cell-cell contacts in brain and in the peripheral nervous system. Plays a role in neurite outgrowth in response to contactin binding. Plays a role in mediating cell-cell contacts between Schwann cells and axons. Plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with GLDN, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier.

Subunit / interactions. Constituent of a NFASC/NRCAM/ankyrin-G complex. Detected in a complex with CNTN1 and PTPRB. Interacts with GLDN/gliomedin. Interacts with MYOC.

Subcellular location. Cell membrane. Cell projection. Axon. Secreted.

Tissue specificity. Detected in all the examined tissues. In the brain it was detected in the amygdala, caudate nucleus, corpus callosum, hippocampus, hypothalamus, substantia nigra, subthalamic nucleus and thalamus.

Disease relevance. Neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS) [MIM:619833] An autosomal recessive disorder characterized by developmental delay apparent from infancy or early childhood, intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Disease severity is highly variable. Most affected individuals have skeletal defects and dysmorphic facial features. Some may have ocular or auditory problems, behavioral abnormalities, and non-specific findings on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the immunoglobulin superfamily. L1/neurofascin/NgCAM family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q92823-1	1	yes
Q92823-2	2
Q92823-3	3
Q92823-4	4
Q92823-5	5
Q92823-6	6

RefSeq proteins (67): NP_001032209, NP_001180511, NP_001180512, NP_001180513, NP_001358048, NP_001358051, NP_001358052, NP_001358053, NP_001358054, NP_001358055, NP_001358056, NP_001358057, NP_001358058, NP_001358059, NP_001358060, NP_001358061, NP_001358062, NP_001358063, NP_001358064, NP_001358065, NP_001358066, NP_001358067, NP_001358068, NP_001358069, NP_001358070, NP_001358071, NP_001358072, NP_001358073, NP_001358074, NP_001358075, NP_001358076, NP_001358077, NP_001358078, NP_001358079, NP_001358080, NP_001358081, NP_001358082, NP_001358083, NP_001358084, NP_001358085, NP_001358086, NP_001358087, NP_001358088, NP_001358089, NP_001358090, NP_001358091, NP_001358092, NP_001358093, NP_001358094, NP_001358095, NP_001358096, NP_001358097, NP_001358098, NP_001358099, NP_001358100, NP_001358101, NP_001358102, NP_001358103, NP_001358104, NP_001358105, NP_001358106, NP_001358107, NP_001358108, NP_001358109, NP_001358110, NP_001358111, NP_005001 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003006	Ig/MHC_CS	Conserved_site
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR026966	Neurofascin/L1/NrCAM_C	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051170	Neural/epithelial_adhesion	Family

Pfam: PF00041, PF07679, PF13882, PF13927

UniProt features (110 total): sequence conflict 20, glycosylation site 18, strand 15, sequence variant 12, domain 11, modified residue 9, splice variant 8, disulfide bond 6, compositionally biased region 3, topological domain 2, signal peptide 1, chain 1, helix 1, region of interest 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1UEN	SOLUTION NMR
1UEY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92823-F1	77.85	0.36

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 (9): 1221, 1225, 1226, 1251, 1254, 1271, 1290, 1291, 1295

Disulfide bonds (6): 68–123, 167–218, 292–340, 382–432, 476–525, 567–616

Glycosylation sites (18): 83, 223, 245, 251, 276, 314, 433, 507, 619, 716, 802, 858, 993, 1009, 1019, 1072, 1083, 1115

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-447038	NrCAM interactions
R-HSA-447043	Neurofascin interactions

MSigDB gene sets: 432 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, GOBP_NEURON_RECOGNITION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, JAEGER_METASTASIS_DN, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, TTCCGTT_MIR191, GOBP_NEURON_MATURATION, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE, MODULE_418, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, GOBP_GROWTH

GO Biological Process (20): angiogenesis (GO:0001525), neuron migration (GO:0001764), axonogenesis (GO:0007409), axon guidance (GO:0007411), axonal fasciculation (GO:0007413), synapse assembly (GO:0007416), central nervous system development (GO:0007417), brain development (GO:0007420), intracellular protein localization (GO:0008104), regulation of neuron projection development (GO:0010975), neuronal action potential propagation (GO:0019227), regulation of axon extension (GO:0030516), retinal ganglion cell axon guidance (GO:0031290), clustering of voltage-gated sodium channels (GO:0045162), positive regulation of neuron differentiation (GO:0045666), cell-cell adhesion (GO:0098609), regulation of postsynapse organization (GO:0099175), cell adhesion (GO:0007155), heterotypic cell-cell adhesion (GO:0034113), synapse organization (GO:0050808)

GO Molecular Function (4): ankyrin binding (GO:0030506), protein binding involved in heterotypic cell-cell adhesion (GO:0086080), cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), axon (GO:0030424), neuron projection (GO:0043005), axon initial segment (GO:0043194), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
L1CAM interactions	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
axon development	2
nervous system development	2
cell-cell adhesion	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell migration	1
generation of neurons	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axonogenesis	1
neuron projection guidance	1
neuron recognition	1
neuron projection fasciculation	1
cell junction assembly	1
synapse organization	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
macromolecule localization	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
transmission of nerve impulse	1
nervous system process	1
action potential propagation	1
regulation of developmental growth	1
axon extension	1
regulation of extent of cell growth	1
axon guidance	1
neuronal ion channel clustering	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
cell adhesion	1
regulation of synapse organization	1
postsynapse organization	1
cellular process	1
cell junction organization	1
cytoskeletal protein binding	1

Protein interactions and networks

STRING

1958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRCAM	GLDN	Q6ZMI3	996
NRCAM	SPTBN4	Q9H254	939
NRCAM	PTPRZ1	P23471	906
NRCAM	ANK3	Q12955	897
NRCAM	CNTN2	P78432	897
NRCAM	CNTN5	O94779	870
NRCAM	CNTNAP4	Q9C0A0	862
NRCAM	ANK2	Q01484	858
NRCAM	SEMA6D	Q8NFY4	845
NRCAM	ANK1	P16157	822
NRCAM	PLXNA1	Q9UIW2	778
NRCAM	HAPLN2	Q9GZV7	760
NRCAM	SEMA3F	Q13275	741
NRCAM	SCN8A	Q9UQD0	691
NRCAM	NFASC	O94856	684

IntAct

21 interactions, top by confidence:

A	B	Type	Score
CNTN1	NRCAM	psi-mi:“MI:0915”(physical association)	0.700
CNTN1	NRCAM	psi-mi:“MI:0407”(direct interaction)	0.700
NRCAM	CNTN1	psi-mi:“MI:0407”(direct interaction)	0.700
NRCAM	CNTN1	psi-mi:“MI:0403”(colocalization)	0.700
FRMD5	FAM234B	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
NFASC	NRCAM	psi-mi:“MI:0915”(physical association)	0.400
HSPA12A	NRCAM	psi-mi:“MI:0915”(physical association)	0.370
NRCAM	HSPA12A	psi-mi:“MI:0915”(physical association)	0.370
NRCAM	MACF1	psi-mi:“MI:0915”(physical association)	0.370
NRCAM	MAGI3	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
valS	NRCAM	psi-mi:“MI:0915”(physical association)	0.000
RSPH1	NRCAM	psi-mi:“MI:0915”(physical association)	0.000
LCOR	NRCAM	psi-mi:“MI:0915”(physical association)	0.000
VPS26C	NRCAM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): NRCAM (Affinity Capture-MS), NRCAM (Affinity Capture-MS), NRCAM (Affinity Capture-RNA), NRCAM (Affinity Capture-MS), NRCAM (Proximity Label-MS), NRCAM (Affinity Capture-MS), NRCAM (Affinity Capture-RNA), PTPRB (Reconstituted Complex), NRCAM (Affinity Capture-MS), NRCAM (Affinity Capture-MS), NRCAM (Reconstituted Complex), NRCAM (Co-fractionation), NRCAM (Co-fractionation), NRCAM (Co-fractionation), NRCAM (Co-fractionation)

ESM2 similar proteins: A0A6I8TCE0, B0X4T2, F1NY98, O00533, O35158, O55005, O60469, O89026, O97394, P12960, P14781, P16092, P17790, P18460, P18461, P21802, P21803, P28685, P29074, P35331, P35832, P57097, P70232, P97686, Q12860, Q12866, Q28106, Q32MD9, Q3UH53, Q4KMG0, Q60805, Q61851, Q63198, Q7Z5N4, Q7ZXX1, Q810U4, Q8AV58, Q8AXZ4, Q8JG38, Q8VHZ8

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IGL7, A5JUY8, A7MBJ4, A8WQH2, B3A0Q8, B3MH43, B3NS99, B4HNW4, B4P5Q9, B4QC63, D3YXG0, G5EBF1, G5EG78, H2A0M7, O01761, O15146, O35158, O55005, O89026, O94779, P05164, P05548, P07202, P09933, P0C5H6, P10586, P11247, P11678, P14650, P16621, P20241, P22079, P28685, P35419, P43146

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
EPHB1	“up-regulates activity”	NRCAM	phosphorylation
EPHB2	“up-regulates activity”	NRCAM	phosphorylation
NRCAM	“up-regulates quantity”	ANK2	relocalization
NRCAM	“up-regulates quantity”	ANK3	relocalization
NRCAM	“up-regulates quantity”	ANK1	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	197
Likely benign	19
Benign	8

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1329980	NM_001037132.4(NRCAM):c.2785C>T (p.Arg929Ter)	Pathogenic
1329981	NM_001037132.4(NRCAM):c.2297_2302delinsTC (p.Thr766fs)	Pathogenic
1329982	NM_001037132.4(NRCAM):c.2647-2A>G	Pathogenic
1329984	NM_001037132.4(NRCAM):c.331G>T (p.Glu111Ter)	Pathogenic
1329985	NM_001037132.4(NRCAM):c.164A>G (p.Asp55Gly)	Pathogenic
1329989	NM_001037132.4(NRCAM):c.1406A>G (p.Asn469Ser)	Pathogenic
1329990	NM_001037132.4(NRCAM):c.2738G>A (p.Gly913Asp)	Pathogenic
1329991	NM_001037132.4(NRCAM):c.590G>A (p.Gly197Asp)	Pathogenic
3911950	NM_001037132.4(NRCAM):c.2903_2904del (p.Leu968fs)	Pathogenic
4711890	NM_001037132.4(NRCAM):c.3454G>T (p.Glu1152Ter)	Pathogenic
1329986	NM_001037132.4(NRCAM):c.230+824G>C	Likely pathogenic
2499480	NM_001037132.4(NRCAM):c.26_29del (p.Lys9fs)	Likely pathogenic
3765746	NM_001037132.4(NRCAM):c.3186del (p.Val1063fs)	Likely pathogenic
4795168	NM_001037132.4(NRCAM):c.3440C>G (p.Ser1147Ter)	Likely pathogenic

SpliceAI

6603 predictions. Top by Δscore:

Variant	Effect	Δscore
7:108150143:CATCA:C	acceptor_gain	1.0000
7:108150144:ATCA:A	acceptor_gain	1.0000
7:108150145:TCA:T	acceptor_gain	1.0000
7:108150146:CA:C	acceptor_gain	1.0000
7:108150146:CAC:C	acceptor_gain	1.0000
7:108150148:C:CC	acceptor_gain	1.0000
7:108150149:T:C	acceptor_loss	1.0000
7:108159457:GCTCA:G	donor_loss	1.0000
7:108159458:CTCA:C	donor_loss	1.0000
7:108159459:TCAC:T	donor_loss	1.0000
7:108159460:CA:C	donor_loss	1.0000
7:108159461:A:C	donor_loss	1.0000
7:108159462:C:CG	donor_loss	1.0000
7:108159537:TTTAA:T	acceptor_gain	1.0000
7:108159539:TAA:T	acceptor_gain	1.0000
7:108159542:C:CC	acceptor_gain	1.0000
7:108160491:CG:C	acceptor_gain	1.0000
7:108168275:A:AC	donor_gain	1.0000
7:108168275:ACTG:A	donor_gain	1.0000
7:108168276:C:CC	donor_gain	1.0000
7:108168276:CTGC:C	donor_gain	1.0000
7:108180224:T:TA	donor_gain	1.0000
7:108181827:AG:A	donor_gain	1.0000
7:108181938:C:CC	acceptor_gain	1.0000
7:108184413:TTACC:T	donor_loss	1.0000
7:108184414:TACC:T	donor_loss	1.0000
7:108184415:A:C	donor_loss	1.0000
7:108184416:C:T	donor_loss	1.0000
7:108184625:C:CT	acceptor_gain	1.0000
7:108184627:C:CT	acceptor_gain	1.0000

AlphaMissense

8576 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:108184475:G:C	N725K	1.000
7:108184475:G:T	N725K	1.000
7:108184491:C:G	R720P	1.000
7:108207553:C:A	W394C	1.000
7:108207553:C:G	W394C	1.000
7:108209584:C:A	W304C	1.000
7:108209584:C:G	W304C	1.000
7:108166983:C:G	R1135P	0.999
7:108178050:A:G	W972R	0.999
7:108178050:A:T	W972R	0.999
7:108180291:A:T	V928D	0.999
7:108181870:C:A	W866C	0.999
7:108181870:C:G	W866C	0.999
7:108181872:A:G	W866R	0.999
7:108181872:A:T	W866R	0.999
7:108182763:A:T	V821D	0.999
7:108182865:C:G	R787P	0.999
7:108184244:C:A	W767C	0.999
7:108184244:C:G	W767C	0.999
7:108184246:A:G	W767R	0.999
7:108184246:A:T	W767R	0.999
7:108184476:T:A	N725I	0.999
7:108184494:A:G	F719S	0.999
7:108184568:C:A	W694C	0.999
7:108184568:C:G	W694C	0.999
7:108189679:C:A	W667C	0.999
7:108189679:C:G	W667C	0.999
7:108189681:A:G	W667R	0.999
7:108189681:A:T	W667R	0.999
7:108191792:A:C	Y614D	0.999

dbSNP variants (sampled 300 via entrez): RS1000007697 (7:108415825 T>C), RS1000017132 (7:108192555 C>T), RS1000023809 (7:108364868 C>T), RS1000025398 (7:108149508 A>C,G), RS1000032951 (7:108409276 A>G), RS1000058110 (7:108308012 T>G), RS1000088354 (7:108184815 G>A), RS1000119595 (7:108185134 G>A), RS1000123579 (7:108456268 G>A), RS1000127153 (7:108399685 T>C), RS1000135960 (7:108227698 C>T), RS1000144435 (7:108415568 A>C,G), RS1000165368 (7:108402950 T>C), RS1000172973 (7:108311334 T>C,G), RS1000181387 (7:108210141 CT>C,CTT)

Disease associations

OMIM: gene MIM:601581 | disease phenotypes: MIM:619833

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with neuromuscular and skeletal abnormalities	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with neuromuscular and skeletal abnormalities (MONDO:0859236)

Orphanet (0):

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000316	Hypertelorism
HP:0000331	Short chin
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000541	Retinal detachment
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000629	Periorbital fullness
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001357	Plagiocephaly
HP:0001385	Hip dysplasia
HP:0001508	Failure to thrive

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001215_4	Coffee consumption	4.000000e-09
GCST001950_5	Femoral neck bone geometry and menarche (age at onset)	5.000000e-08
GCST003013_23	White matter hyperintensity burden	1.000000e-07
GCST003245_8	White matter hyperintensities in ischemic stroke	2.000000e-06
GCST005956_26	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST005962_48	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST006585_2689	Blood protein levels	6.000000e-06
GCST007094_62	Diastolic blood pressure	5.000000e-06
GCST007099_222	Systolic blood pressure	5.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004330	coffee consumption
EFO:0004704	age at menopause
EFO:0005665	white matter hyperintensity measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
sodium arsenite	decreases expression, increases expression	3
bisphenol F	increases methylation, increases expression, affects cotreatment	2
bisphenol A	decreases expression, increases expression	2
sodium arsenate	decreases expression, increases abundance, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Arsenic	increases expression, affects expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Indomethacin	increases expression, decreases expression, affects cotreatment	2
Nickel	increases expression	2
Silicon Dioxide	affects secretion, increases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
lead acetate	increases expression	1
trichostatin A	decreases expression, increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tobacco tar	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
brequinar	increases expression	1
azoxystrobin	decreases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
deguelin	decreases expression	1

Clinical trials (associated diseases)

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