CHL1

Summary

CHL1 (cell adhesion molecule L1 like, HGNC:1939) is a protein-coding gene on chromosome 3p26.3, encoding Neural cell adhesion molecule L1-like protein (O00533). Extracellular matrix and cell adhesion protein that plays a role in nervous system development and in synaptic plasticity.

The protein encoded by this gene is a member of the L1 gene family of neural cell adhesion molecules. It is a neural recognition molecule that may be involved in signal transduction pathways. The deletion of one copy of this gene may be responsible for mental defects in patients with 3p- syndrome. This protein may also play a role in the growth of certain cancers. Alternate splicing results in both coding and non-coding variants.

Source: NCBI Gene 10752 — RefSeq curated summary.

At a glance

• Gene–disease (curated): partial deletion of the short arm of chromosome 3 (Limited, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 419 total — 2 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_006614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1939
Approved symbol	CHL1
Name	cell adhesion molecule L1 like
Location	3p26.3
Locus type	gene with protein product
Status	Approved
Aliases	CALL, L1CAM2, FLJ44930, MGC132578
Ensembl gene	ENSG00000134121
Ensembl biotype	protein_coding
OMIM	607416
Entrez	10752

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 7 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000256509, ENST00000397491, ENST00000421198, ENST00000427688, ENST00000435603, ENST00000445697, ENST00000449294, ENST00000453040, ENST00000461289, ENST00000470005, ENST00000470880, ENST00000471332, ENST00000481167, ENST00000486881, ENST00000489224, ENST00000620033

RefSeq mRNA: 3 — MANE Select: NM_006614 NM_001253387, NM_001253388, NM_006614

CCDS: CCDS2556, CCDS58812, CCDS74887

Canonical transcript exons

ENST00000256509 — 28 exons

Exon	Start	End
ENSE00000912307	342984	343031
ENSE00000912326	401626	401698
ENSE00001329621	405495	409417
ENSE00001829282	244613	244692
ENSE00001939343	196763	197063
ENSE00003497221	377818	377942
ENSE00003511168	390701	390816
ENSE00003530751	341912	342082
ENSE00003538417	399017	399148
ENSE00003545363	398227	398385
ENSE00003552861	344589	344709
ENSE00003561770	328167	328354
ENSE00003576786	354640	354771
ENSE00003595167	349359	349543
ENSE00003596320	382179	382280
ENSE00003601757	361699	361810
ENSE00003607064	389252	389474
ENSE00003608680	391675	391797
ENSE00003610686	390955	391159
ENSE00003629560	360284	360424
ENSE00003632463	382474	382671
ENSE00003635718	365950	366115
ENSE00003655775	383816	383886
ENSE00003662781	319683	319867
ENSE00003677963	363217	363383
ENSE00003689547	394693	394872
ENSE00003691296	340794	340916
ENSE00003789563	325959	326064

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.19.

FANTOM5 (CAGE): breadth broad, TPM avg 9.9931 / max 560.5642, expressed in 384 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34966	2.5597	244
34967	2.2374	251
34969	1.6437	276
34965	1.5196	208
34972	0.9185	108
34963	0.5038	122
34970	0.1563	69
34968	0.1488	89
202651	0.1197	65
34964	0.0839	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.57	gold quality
endothelial cell	CL:0000115	98.01	gold quality
superior frontal gyrus	UBERON:0002661	97.62	gold quality
sural nerve	UBERON:0015488	97.32	gold quality
dorsal root ganglion	UBERON:0000044	97.20	gold quality
postcentral gyrus	UBERON:0002581	96.92	gold quality
frontal pole	UBERON:0002795	96.91	gold quality
parietal lobe	UBERON:0001872	96.86	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.83	gold quality
trigeminal ganglion	UBERON:0001675	96.75	gold quality
nerve	UBERON:0001021	96.23	gold quality
tibial nerve	UBERON:0001323	96.23	gold quality
middle temporal gyrus	UBERON:0002771	96.14	gold quality
CA1 field of hippocampus	UBERON:0003881	95.91	gold quality
entorhinal cortex	UBERON:0002728	95.66	gold quality
orbitofrontal cortex	UBERON:0004167	95.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.34	gold quality
substantia nigra pars compacta	UBERON:0001965	94.78	gold quality
colonic epithelium	UBERON:0000397	94.67	gold quality
occipital lobe	UBERON:0002021	94.61	gold quality
prefrontal cortex	UBERON:0000451	94.55	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.37	gold quality
superior vestibular nucleus	UBERON:0007227	94.32	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.30	gold quality
primary visual cortex	UBERON:0002436	94.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.09	gold quality
frontal cortex	UBERON:0001870	93.82	gold quality
neocortex	UBERON:0001950	93.54	gold quality
cerebral cortex	UBERON:0000956	93.53	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	1666.54
E-GEOD-75140	yes	760.47
E-ENAD-20	yes	389.17
E-HCAD-35	yes	66.96
E-GEOD-135922	yes	29.87
E-CURD-119	yes	29.27
E-GEOD-84465	yes	25.19
E-HCAD-4	yes	18.53
E-MTAB-8410	yes	16.77
E-HCAD-25	yes	16.51
E-CURD-46	yes	9.12
E-CURD-112	yes	9.11
E-MTAB-9543	no	2023.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

247 targeting CHL1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
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

Literature-anchored findings (GeneRIF, showing 31)

• An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. (PMID:11986985)
• L1 could drive progression by enhancing cell migration and tumor growth in ovarian carcinoma. (PMID:15704102)
• MAP kinase pathway regulates L1-CAM-mediated nerve growth by modulating ankyrin binding. (PMID:16597699)
• CHL1 expression was uniformly positive on a cell line derived from angiomyolipoma. (PMID:17592550)
• results do not support the candidacy of CHL1, CNTN6, and CNTN4 as tumor suppressor genes in the 3p26-pter region in ovarian cancer (PMID:19509545)
• Genome-wide transcriptional profiling of in vitro phenotyped LCLs identified CHL1 and additional genes implicated in synaptogenesis and brain circuitry as putative SSRI response biomarkers. (PMID:21332311)
• CHL1 is involved in the development of different human cancers. (PMID:21408220)
• miR-10a expression is upregulated in cervical cancer tissues, and miR-10a promotes cell growth, migration and invasion by targeting CHL1 in human cervical cancer cells. (PMID:22634495)
• Overall, our study found a significant association of IL-17RC gene polymorphisms with AIS in a Chinese Han population, indicating IL-17RC gene may be as a susceptibility gene for AIS. (PMID:22744455)
• The miRNA miR-151-3p had 6.7-fold higher basal expression in paroxetine-sensitive LCLs. This corresponds with lower expression of CHL1, a target of miR-151-3p (PMID:22909203)
• BACE1(-/-) axon guidance defects are likely the result of abrogated BACE1 processing of CHL1 and BACE1 deficiency produces a CHL1 loss-of-function phenotype (PMID:22988240)
• The rs2272522 polymorphism (in the CHL1 gene) was found to exhibit a highly significant association with schizophrenia in the Qatari population. (PMID:23857787)
• CHL1 has a role in human breast tumorigenesis and progression (PMID:23906755)
• In 1 of 113 Colombian children with refractory epilepsy, MLPA showed a subtelomeric duplication of exon 3 of CHL1, also present in 2 relatives. (PMID:24203666)
• our findings suggest that miR-590-5p acts as an oncogene by targeting the CHL1 gene and promotes cervical cancer proliferation (PMID:24288179)
• There was no statistical association between polymorphisms of the CHL1 gene and idiopathic scoliosis in a Chinese population. (PMID:24512353)
• Our data collectively indicate that miR-182 in PTC promotes cell proliferation and invasion through direct suppression of CHL1, supporting the potential utility of miR-182 inhibition as a novel therapeutic strategy against PTC. (PMID:24971532)
• CHL1 expression patient-derived lymphoblasts correlated with clinical outcome in depressive disorder patients. (PMID:25943212)
• Results indicate that close homolog of L1 protein (CHL1) is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in breast cancer (BC). (PMID:28178655)
• Expression level of miR-21-5p increased in both colon adenocarcinoma (COAD) tissues and cells. The result of in vivo experiments showed that down-regulation of miR-21-5p decreased the volume and weight of tumor, while knockdown of CHLI stimulated tumor growth. The overexpression of miR-21-5p can promote propagation and invasiveness of (COAD) cells through inhibiting the expression of CHL1. (PMID:30134821)
• CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase million in HCC compared with benign Hurthle cell tumors. This was confirmed by qRT-PCR. Moreover, the immunoreactivity score of the CHL1 protein was significantly higher in HCC compared with benign Hurthle cell nodules. (PMID:30311656)
• Results identified a new tumor suppressor, CHL1, located at 3p26 which was frequently deleted in esophageal squamous cells carcinoma (ESCC). Reduced expression of CHL1 correlated with poor differentiation, increased invasion, lymph-node metastasis, advanced tumor stage, and decreased overall survival. Further data support CHL1 as an important tumor suppressor with both anti-proliferation and anti-metastasis abilities. (PMID:30622339)
• CHL1 expression levels were significantly higher in ovarian endometriosis tissue than in eutopic endometrium. (PMID:30943448)
• The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination. (PMID:31372722)
• Reduced Expression of Chl1 gene Impairs Insulin Secretion by Down-Regulating the Expression of Key Molecules of beta-cell Function. (PMID:31614370)
• Downregulation of Adhesion Molecule CHL1 in B Cells but Not T Cells of Patients with Major Depression and in the Brain of Mice with Chronic Stress. (PMID:32557322)
• Analysis of the functional sequences in the promoter region of the human adhesion molecule close homolog of L1. (PMID:33054469)
• Ezrin interacts with the tumor suppressor CHL1 and promotes neuronal differentiation of human neuroblastoma. (PMID:33326488)
• Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism. (PMID:33453020)
• Exosomal miR-338-3p suppresses non-small-cell lung cancer cells metastasis by inhibiting CHL1 through the MAPK signaling pathway. (PMID:34718336)
• Expression of CHL1 in Clear Cell Renal Cell Carcinoma and its Association With Prognosis. (PMID:35262525)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	chl1a	ENSDARG00000077881
mus_musculus	Chl1	ENSMUSG00000030077
rattus_norvegicus	Chl1	ENSRNOG00000045771

Paralogs (36): CNTN1 (ENSG00000018236), CDON (ENSG00000064309), NEO1 (ENSG00000067141), SDK2 (ENSG00000069188), IGSF9B (ENSG00000080854), IGSF9 (ENSG00000085552), NRCAM (ENSG00000091129), MXRA5 (ENSG00000101825), IGDCC4 (ENSG00000103742), CNTN3 (ENSG00000113805), IGSF21 (ENSG00000117154), CNTN6 (ENSG00000134115), 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

Neural cell adhesion molecule L1-like protein — O00533 (reviewed: O00533)

Alternative names: Close homolog of L1

All UniProt accessions (8): A0A087X0M8, C9J905, C9JEY3, O00533, C9JH37, C9JW79, F8WEP4, H7C0J0

UniProt curated annotations — full annotation on UniProt →

Function. Extracellular matrix and cell adhesion protein that plays a role in nervous system development and in synaptic plasticity. Both soluble and membranous forms promote neurite outgrowth of cerebellar and hippocampal neurons and suppress neuronal cell death. Plays a role in neuronal positioning of pyramidal neurons and in regulation of both the number of interneurons and the efficacy of GABAergic synapses. May play a role in regulating cell migration in nerve regeneration and cortical development. Potentiates integrin-dependent cell migration towards extracellular matrix proteins. Recruits ANK3 to the plasma membrane.

Subunit / interactions. May interact with L1CAM. May interact with ITGB1/ITGA1 heterodimer and ITGB1/ITGA2 heterodimer as well as with ANK3.

Subcellular location. Cell membrane Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in the fetal and adult brain as well as in Schwann cell culture. Also detected in adult peripheral tissues.

Post-translational modifications. Cleavage by metalloprotease ADAM8 in the extracellular part generates 2 soluble forms (125 kDa and 165 kDa) in vitro and is inhibited by metalloprotease inhibitors. Cleaved by BACE1. N-glycosylated. Contains N-linked oligosaccharides with a sulfated carbohydrate structure type HNK-1 (SO4-3-GlcUABeta1,3GalBeta1,4GlcNAc). O-glycosylated.

Domain organisation. The FIG[AQ]Y motif seems to be an ankyrin recruitment region. The DGEA motif seems to be a recognition site for integrin.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O00533-1	1	yes
O00533-2	2

RefSeq proteins (3): NP_001240316, NP_001240317, NP_006605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013151	Immunoglobulin_dom	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, PF00047, PF07679, PF13882, PF13927

UniProt features (49 total): domain 10, glycosylation site 10, disulfide bond 6, sequence variant 4, region of interest 3, modified residue 3, chain 2, short sequence motif 2, compositionally biased region 2, site 2, topological domain 2, signal peptide 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00533-F1	78.37	0.40

Functional residue map

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

Catalytic / active sites (2): 753–754 (cleavage; by adam8); 1039–1040 (cleavage; by adam8)

Post-translational modifications (3): 1147, 1160, 1180

Disulfide bonds (6): 57–109, 153–204, 262–310, 352–401, 445–494, 536–591

Glycosylation sites (10): 299, 476, 482, 562, 580, 767, 822, 945, 1026, 231

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-447041	CHL1 interactions
R-HSA-1266738	Developmental Biology
R-HSA-373760	L1CAM interactions
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 267 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_COGNITION, GOBP_BEHAVIOR, MCLACHLAN_DENTAL_CARIES_UP, MODULE_255, GOBP_ADULT_BEHAVIOR, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, MODULE_317, GOBP_NEUROGENESIS, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, MODULE_66, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, SOX9_B1

GO Biological Process (11): neuron migration (GO:0001764), cell adhesion (GO:0007155), signal transduction (GO:0007165), axon guidance (GO:0007411), adult locomotory behavior (GO:0008344), exploration behavior (GO:0035640), negative regulation of neuron apoptotic process (GO:0043524), cognition (GO:0050890), nervous system development (GO:0007399), cell differentiation (GO:0030154), neuron projection development (GO:0031175)

GO Molecular Function (2): protease binding (GO:0002020), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), membrane (GO:0016020), dendrite (GO:0030425), neuron projection (GO:0043005), apical part of cell (GO:0045177), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
L1CAM interactions	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	2
cell migration	1
generation of neurons	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
axonogenesis	1
neuron projection guidance	1
locomotory behavior	1
adult behavior	1
behavior	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
nervous system process	1
system development	1
cellular developmental process	1
neuron development	1
plasma membrane bounded cell projection organization	1
enzyme binding	1
binding	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
plasma membrane bounded cell projection	1
extracellular vesicle	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHL1	CNTN6	Q9UQ52	691
CHL1	CNTNAP4	Q9C0A0	665
CHL1	SEMA3A	Q14563	647
CHL1	RDX	P35241	542
CHL1	EZR	P15311	540
CHL1	NRP1	O14786	520
CHL1	CNTN5	O94779	503
CHL1	SPTBN1	Q01082	483
CHL1	BACE1	P56817	437
CHL1	UHRF2	Q96PU4	380
CHL1	KANK1	Q14678	377
CHL1	NRG1	P98202	356
CHL1	ANK3	Q12955	347
CHL1	ANK2	Q01484	345
CHL1	SLC27A4	Q6P1M0	345

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CHL1	L1CAM	psi-mi:“MI:0915”(physical association)	0.680
CHL1	L1CAM	psi-mi:“MI:0407”(direct interaction)	0.680
CHL1	CHL1	psi-mi:“MI:0407”(direct interaction)	0.560
CHL1	LGALS1	psi-mi:“MI:0914”(association)	0.530
CNTN5	CHL1	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	CHL1	psi-mi:“MI:0915”(physical association)	0.400
FERMT2	CHL1	psi-mi:“MI:0915”(physical association)	0.000
E2F1	CHL1	psi-mi:“MI:0915”(physical association)	0.000
JUN	CHL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): ANK1 (Affinity Capture-MS), ANK3 (Affinity Capture-MS), ANK2 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), CNTN6 (Affinity Capture-Western), CHL1 (Affinity Capture-Western), CHL1 (Affinity Capture-Western), RSL1D1 (Proximity Label-MS), ANK2 (Affinity Capture-MS), ANK3 (Affinity Capture-MS), ANK1 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), CHL1 (Affinity Capture-MS)

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: A0A6I8TCE0, A2A8L5, A2AJX4, A7MBJ4, B0X4T2, B3EWZ5, B3EWZ6, B3EX02, B7T7N1, F1NWE3, O00533, O15197, P0C0K6, P10586, P13944, P14781, P23468, P29317, P35331, P35832, P60755, P60756, P70232, P85171, P97686, P98073, Q07497, Q0PMG2, Q0WYX8, Q13332, Q1KL86, Q28902, Q3UH53, Q58EX2, Q5VYJ5, Q60ZN5, Q61330, Q64487, Q64604, Q6V4S5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CHL1	“up-regulates quantity”	ANK2	relocalization
CHL1	“up-regulates quantity”	ANK3	relocalization
CHL1	“up-regulates quantity”	ANK1	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	8
Uncertain significance	303
Likely benign	48
Benign	22

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
145577	GRCh38/hg38 3p26.3(chr3:52266-868393)x3	Pathogenic
562685	GRCh37/hg19 3p26.3-26.1(chr3:61891-4098164)x1	Pathogenic
150610	GRCh38/hg38 3p26.3-26.2(chr3:32241-3355776)x1	Likely pathogenic
253369	GRCh37/hg19 3p26.3-26.2(chr3:270649-3927005)x1	Likely pathogenic
393803	GRCh37/hg19 3p26.3(chr3:315102-1125700)x1	Likely pathogenic
545299	Single allele	Likely pathogenic
562698	GRCh37/hg19 3p26.3(chr3:115780-320034)x1	Likely pathogenic
562700	GRCh37/hg19 3p26.3(chr3:242240-556260)x1	Likely pathogenic
814387	GRCh37/hg19 3p26.3(chr3:61891-1717877)x1	Likely pathogenic
997052	GRCh37/hg19 3p26.3-26.1(chr3:73914-4331711)	Likely pathogenic

SpliceAI

4912 predictions. Top by Δscore:

Variant	Effect	Δscore
3:285270:G:GT	donor_gain	1.0000
3:285286:C:G	donor_gain	1.0000
3:326061:CAACG:C	donor_loss	1.0000
3:326062:AACG:A	donor_loss	1.0000
3:326063:AC:A	donor_gain	1.0000
3:326063:ACG:A	donor_loss	1.0000
3:326064:CGTG:C	donor_loss	1.0000
3:326065:G:A	donor_loss	1.0000
3:326065:G:GG	donor_gain	1.0000
3:326066:T:G	donor_loss	1.0000
3:326067:G:GC	donor_loss	1.0000
3:326068:AG:A	donor_loss	1.0000
3:328162:TTTAG:T	acceptor_loss	1.0000
3:328164:TA:T	acceptor_loss	1.0000
3:328165:A:AG	acceptor_gain	1.0000
3:328165:A:AT	acceptor_loss	1.0000
3:328166:G:GA	acceptor_loss	1.0000
3:328166:G:GG	acceptor_gain	1.0000
3:328204:A:AG	acceptor_gain	1.0000
3:328205:C:G	acceptor_gain	1.0000
3:328350:TCCAA:T	donor_gain	1.0000
3:328351:CCAA:C	donor_gain	1.0000
3:328351:CCAAG:C	donor_loss	1.0000
3:328352:CAA:C	donor_gain	1.0000
3:328354:AGT:A	donor_loss	1.0000
3:328355:G:A	donor_loss	1.0000
3:328355:G:GG	donor_gain	1.0000
3:328356:T:G	donor_loss	1.0000
3:342080:GTT:G	donor_gain	1.0000
3:342083:G:GG	donor_gain	1.0000

AlphaMissense

8054 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:328176:G:C	W69C	1.000
3:328176:G:T	W69C	1.000
3:340906:G:C	W166C	1.000
3:340906:G:T	W166C	1.000
3:349380:G:C	W274C	1.000
3:349380:G:T	W274C	1.000
3:354651:T:A	W333R	1.000
3:354651:T:C	W333R	1.000
3:354653:G:C	W333C	1.000
3:354653:G:T	W333C	1.000
3:354744:T:A	W364R	1.000
3:354744:T:C	W364R	1.000
3:354746:G:C	W364C	1.000
3:354746:G:T	W364C	1.000
3:360361:T:G	Y399D	1.000
3:360381:T:A	N405K	1.000
3:360381:T:G	N405K	1.000
3:363217:G:C	W457C	1.000
3:363217:G:T	W457C	1.000
3:366068:G:C	W552C	1.000
3:366068:G:T	W552C	1.000
3:383881:T:A	W732R	1.000
3:383881:T:C	W732R	1.000
3:383883:G:C	W732C	1.000
3:383883:G:T	W732C	1.000
3:328174:T:A	W69R	0.999
3:328174:T:C	W69R	0.999
3:328288:T:G	Y107D	0.999
3:328292:G:C	R108P	0.999
3:328294:T:A	C109S	0.999

dbSNP variants (sampled 300 via entrez): RS1000007793 (3:279067 G>A,T), RS1000021135 (3:222544 G>A,C), RS1000025436 (3:302471 T>C), RS1000040903 (3:306865 A>G), RS1000041690 (3:336040 C>G,T), RS1000048505 (3:199094 C>T), RS1000082065 (3:276911 A>C,G), RS1000085372 (3:217175 A>G), RS1000091066 (3:365828 G>A,T), RS1000096669 (3:396591 G>A,C,T), RS1000096776 (3:370898 T>C), RS1000099587 (3:340821 T>A,C), RS1000106303 (3:225213 T>C), RS1000109965 (3:370382 A>G), RS1000118926 (3:246625 G>A)

Disease associations

OMIM: gene MIM:607416 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
partial deletion of the short arm of chromosome 3	Limited	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (4): primary ovarian failure (MONDO:0005387), autism (MONDO:0005260), partial deletion of the short arm of chromosome 3 (MONDO:0016885), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D065886	Neurodevelopmental Disorders	F03.625
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	decreases reaction, affects cotreatment, increases expression, affects expression	4
Vorinostat	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Amphotericin B	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Lead	affects splicing	1
Methyl Methanesulfonate	decreases expression	1
Nickel	decreases reaction, affects expression	1
Testosterone	decreases expression	1
Aflatoxin B1	increases methylation	1
Paroxetine	affects response to substance	1
Asbestos, Serpentine	increases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments