ADGRL1

Summary

ADGRL1 (adhesion G protein-coupled receptor L1, HGNC:20973) is a protein-coding gene on chromosome 19p13.12, encoding Adhesion G protein-coupled receptor L1 (O94910). Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells.

This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane. Latrophilin-1 has been shown to recruit the neurotoxin from black widow spider venom, alpha-latrotoxin, to the synapse plasma membrane. Alternative splicing results in multiple variants encoding distinct isoforms.

Source: NCBI Gene 22859 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental delay, behavioral abnormalities, and neuropsychiatric disorders (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 333 total — 13 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_014921

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20973
Approved symbol	ADGRL1
Name	adhesion G protein-coupled receptor L1
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0821, CIRL1, LEC2
Ensembl gene	ENSG00000072071
Ensembl biotype	protein_coding
OMIM	616416
Entrez	22859

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000340736, ENST00000361434, ENST00000588677, ENST00000589616, ENST00000590223, ENST00000591528, ENST00000592164, ENST00000593005, ENST00000963580, ENST00000963581

RefSeq mRNA: 2 — MANE Select: NM_014921 NM_001008701, NM_014921

CCDS: CCDS12307, CCDS32928

Canonical transcript exons

ENST00000361434 — 23 exons

Exon	Start	End
ENSE00000341216	14160112	14160297
ENSE00000341218	14159401	14159584
ENSE00000341226	14155359	14155527
ENSE00000685690	14152309	14152437
ENSE00000685693	14152517	14152613
ENSE00000685697	14152784	14152912
ENSE00000685718	14157882	14158052
ENSE00000685721	14158338	14158552
ENSE00000685723	14159090	14159215
ENSE00000685783	14161312	14161626
ENSE00000836546	14156110	14156201
ENSE00000836547	14156658	14156724
ENSE00001055534	14170682	14170791
ENSE00001055541	14177531	14177744
ENSE00001126108	14157251	14157460
ENSE00001126148	14160593	14160696
ENSE00001139375	14162606	14163406
ENSE00001182806	14156925	14157145
ENSE00001368324	14183533	14183697
ENSE00001412099	14205985	14206169
ENSE00001659204	14152133	14152150
ENSE00002798189	14147743	14151615
ENSE00003559561	14159735	14159773

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.07.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8947 / max 114.8289, expressed in 775 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179627	1.8848	775
179626	0.0099	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.07	gold quality
cerebellum	UBERON:0002037	95.71	gold quality
cerebellar cortex	UBERON:0002129	95.67	gold quality
cerebellar hemisphere	UBERON:0002245	95.67	gold quality
cortical plate	UBERON:0005343	95.66	gold quality
superior frontal gyrus	UBERON:0002661	95.26	gold quality
primary visual cortex	UBERON:0002436	95.12	gold quality
right frontal lobe	UBERON:0002810	94.42	gold quality
frontal cortex	UBERON:0001870	94.25	gold quality
prefrontal cortex	UBERON:0000451	93.99	gold quality
cerebral cortex	UBERON:0000956	93.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.43	gold quality
anterior cingulate cortex	UBERON:0009835	93.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.18	gold quality
brain	UBERON:0000955	92.81	gold quality
Ammon’s horn	UBERON:0001954	92.76	gold quality
temporal lobe	UBERON:0001871	92.70	gold quality
amygdala	UBERON:0001876	92.61	gold quality
putamen	UBERON:0001874	92.34	gold quality
nucleus accumbens	UBERON:0001882	92.20	gold quality
caudate nucleus	UBERON:0001873	91.50	gold quality
ventricular zone	UBERON:0003053	91.02	gold quality
ganglionic eminence	UBERON:0004023	90.85	gold quality
hypothalamus	UBERON:0001898	90.34	gold quality
pituitary gland	UBERON:0000007	90.27	gold quality
adenohypophysis	UBERON:0002196	90.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.22	gold quality
substantia nigra	UBERON:0002038	88.72	gold quality
body of uterus	UBERON:0009853	87.89	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

165 targeting ADGRL1, 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-4455	100.00	65.48	1587
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-424-5P	99.89	71.90	2641

Literature-anchored findings (GeneRIF, showing 10)

• In this article they evaluated the amount of p120-p85 complex still presented on the cellular membrane and confirmed that on cell surface major amount of mature CIRL-1 presented as a p120-p85 subunit complex. (PMID:20971062)
• Data suggest teneurin-1/TENM1 (and possibly TENM3) undergoes proteolysis to TCAPs (teneurin C-terminal associated peptides) that form intercellular adhesive units with latrophilin; signaling via TENM1 TCAPs appears to regulate reproduction. [REVIEW] (PMID:26485751)
• Our findings demonstrate that latrophilin-1 could be considered as a novel biomarker of human acute myeloid leukaemia (PMID:27322212)
• A single SNP in LPHN1 (rs3810256) was identified, with the minor allele increasing the risk of asthma. (PMID:27325752)
• Cortisol facilitates the immune escape of human acute myeloid leukemia cells by inducing latrophilin 1 expression. (PMID:29907881)
• alterations in latrophilin expression occur in AML cells expressing P-gp (PMID:29938681)
• These findings reveal a novel mechanism of axonal pathfinding, whereby latrophilin-1 and Lasso mediate both short-range interaction that supports synaptogenesis, and long-range signaling that induces axonal attraction. (PMID:30457553)
• results suggest that SSB splicing selectively affects the duality of LPHN1 signaling toward opposing cAMP pathways (PMID:31339586)
• ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model. (PMID:35907405)
• Dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity. (PMID:38664368)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000112310
mus_musculus	Adgrl1	ENSMUSG00000013033
rattus_norvegicus	Adgrl1	ENSRNOG00000029134

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Adhesion G protein-coupled receptor L1 — O94910 (reviewed: O94910)

Alternative names: Calcium-independent alpha-latrotoxin receptor 1, Latrophilin-1, Lectomedin-2

All UniProt accessions (4): O94910, K7EK47, K7ERC3, K7ESH3

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. Receptor for TENM2 that mediates heterophilic synaptic cell-cell contact and postsynaptic specialization. Receptor probably implicated in the regulation of exocytosis.

Subunit / interactions. Forms a heterodimer, consisting of a large extracellular region (p120) non-covalently linked to a seven-transmembrane moiety (p85). Interacts with syntaxin and with proteins of the SHANK family via the PDZ domain. Interacts (via extracellular domain) with FLRT1, FLRT2 and FLRT3 (via extracellular domain).

Subcellular location. Cell membrane. Cell projection. Axon. Growth cone. Synapse. Presynaptic cell membrane. Synaptosome.

Post-translational modifications. Autoproteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit. This proteolytic processing takes place early in the biosynthetic pathway, either in the endoplasmic reticulum or in the early compartment of the Golgi apparatus.

Disease relevance. Developmental delay, behavioral abnormalities, and neuropsychiatric disorders (DEDBANP) [MIM:620065] An autosomal dominant disorder characterized by mild global developmental delay, normal or variably impaired intellectual development, and behavioral or neuropsychiatric disorders, including autism spectrum disorder, attention deficit-hyperactivity disorder, and executive functioning deficits. Additional features may include speech delay, dysmorphic features, hypotonia, sleep disturbances, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The extracellular domain coupled to the a single transmembrane region are sufficient for full responsiveness to alpha-latrotoxin.

Similarity. Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O94910-1	1	yes
O94910-2	2

RefSeq proteins (2): NP_001008701, NP_055736* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000203	GPS	Conserved_site
IPR000832	GPCR_2_secretin-like	Family
IPR000922	Lectin_gal-bd_dom	Domain
IPR001879	GPCR_2_extracellular_dom	Domain
IPR003112	Olfac-like_dom	Domain
IPR003334	GPCR_2_latrophilin_rcpt_C	Domain
IPR003924	GPCR_2_latrophilin	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR031234	Latrophilin-1_TM	Domain
IPR032471	AGRL2-4_GAIN_subdom_A	Domain
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR043159	Lectin_gal-bd_sf	Homologous_superfamily
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF01825, PF02140, PF02191, PF02354, PF02793, PF16489

UniProt features (62 total): disulfide bond 9, sequence variant 9, topological domain 8, transmembrane region 7, glycosylation site 7, region of interest 6, domain 3, compositionally biased region 3, modified residue 3, binding site 2, signal peptide 1, chain 1, site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94910-F1	70.63	0.35

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 (1): 838–839 (cleavage; by autolysis)

Ligand- & substrate-binding residues (2): 42; 117–120

Post-translational modifications (3): 1194, 1220, 1473

Disulfide bonds (9): 41–71, 50–128, 83–115, 96–102, 140–322, 480–515, 503–532, 802–833, 821–835

Glycosylation sites (7): 98, 531, 640, 742, 801, 806, 827

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 272 (showing top): TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, TGACCTY_ERR1_Q2, FOXO4_01, YY1_Q6, GGCNKCCATNK_UNKNOWN, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, GTGCCTT_MIR506, BROWNE_HCMV_INFECTION_24HR_UP, ONKEN_UVEAL_MELANOMA_UP, MODULE_289, TATCTGG_MIR488, MORF_RAP1A, TCCAGAG_MIR518C, VDR_Q3

GO Biological Process (3): cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), signal transduction (GO:0007165)

GO Molecular Function (6): G protein-coupled receptor activity (GO:0004930), latrotoxin receptor activity (GO:0016524), carbohydrate binding (GO:0030246), cell adhesion molecule binding (GO:0050839), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (8): plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), growth cone (GO:0030426), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), synapse (GO:0045202), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
transmembrane signaling receptor activity	2
binding	2
cellular anatomical structure	2
G protein-coupled receptor activity	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor signaling pathway	1
protein binding	1
signaling receptor activity	1
membrane	1
cell periphery	1
neuron projection	1
site of polarized growth	1
distal axon	1
synaptic membrane	1
presynapse	1
plasma membrane bounded cell projection	1
cell junction	1

Protein interactions and networks

STRING

1540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRL1	TENM2	Q9NT68	971
ADGRL1	SLC35A1	P78382	969
ADGRL1	TENM4	Q6N022	840
ADGRL1	FLRT3	Q9NZU0	733
ADGRL1	SLC35D3	Q5M8T2	727
ADGRL1	NRXN1	Q9ULB1	711
ADGRL1	SLC35D2	Q76EJ3	689
ADGRL1	SLC35D1	Q9NTN3	677
ADGRL1	NRXN2	Q9P2S2	669
ADGRL1	ABI3	Q9P2A4	663
ADGRL1	TENM1	Q9UKZ4	617
ADGRL1	FLRT1	Q9NZU1	605
ADGRL1	GNAQ	P50148	550
ADGRL1	FLRT2	O43155	548
ADGRL1	SHANK2	Q9UPX8	541

IntAct

61 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
FLRT1	TCAF2	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
HAX1	CHEK1	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
CACNA1A	ADGRL1	psi-mi:“MI:0915”(physical association)	0.510
ADGRL1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PCDHA12	KLRG2	psi-mi:“MI:0914”(association)	0.350
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350
NKAIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350
TMEM130	GOLIM4	psi-mi:“MI:0914”(association)	0.350
VNN2	ATP2A1	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): LPHN1 (Two-hybrid), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS), LPHN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0Q3IBS1, I1H0V9, O08619, O18733, O54732, O82088, O88917, O94910, O97831, P00488, P08587, P13696, P14780, P22735, P22758, P23606, P30086, P31044, P41245, P41246, P51176, P51511, P52176, P52181, P52183, P54185, P93003, Q3YIX4, Q41261, Q5R4R0, Q656A5, Q80TR1, Q8MK67, Q8VIN1, Q8VWH2, Q93WI9, Q95220, Q9ASJ1, Q9D9G2, Q9FIT4

Diamond homologs: A2BD09, A4IIT5, A6QLD2, B0BNI5, B5MFE9, O70624, O88917, O88923, O88998, O94910, O95490, O95897, O97817, O97827, O97831, P63056, P63057, Q0P3W2, Q0V9V5, Q0VCP3, Q25C36, Q2PT31, Q3UZZ4, Q3V1G4, Q568Y7, Q594P2, Q62609, Q66H86, Q68BL7, Q68BL8, Q6UWY5, Q6UX06, Q80TR1, Q80TS3, Q863A3, Q866N2, Q8BHP7, Q8BK62, Q8BM13, Q8JZZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	14
Uncertain significance	227
Likely benign	45
Benign	1

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1700599	NM_014921.5(ADGRL1):c.2998T>C (p.Trp1000Arg)	Pathogenic
1700600	NM_014921.5(ADGRL1):c.3440T>C (p.Met1147Thr)	Pathogenic
1700601	NM_014921.5(ADGRL1):c.3391C>T (p.Arg1131Ter)	Pathogenic
1700604	NM_014921.5(ADGRL1):c.3476C>T (p.Ser1159Phe)	Pathogenic
1700605	NM_014921.5(ADGRL1):c.2049dup (p.Glu684fs)	Pathogenic
1700606	NM_014921.5(ADGRL1):c.3517C>T (p.Arg1173Ter)	Pathogenic
2663877	NM_014921.5(ADGRL1):c.3256dup (p.Val1086fs)	Pathogenic
3063758	NM_014921.5(ADGRL1):c.2270_2271del (p.Val757fs)	Pathogenic
3087198	NM_014921.5(ADGRL1):c.2567C>A (p.Ser856Ter)	Pathogenic
3087220	NM_014921.5(ADGRL1):c.3414_3415del (p.Gly1139fs)	Pathogenic
3087350	NM_014921.5(ADGRL1):c.614_615insGTTG (p.Val206fs)	Pathogenic
4017086	NM_014921.5(ADGRL1):c.1507C>T (p.Arg503Ter)	Pathogenic
4819168	NM_014921.5(ADGRL1):c.283_284del (p.Arg95fs)	Pathogenic
1700603	NM_014921.5(ADGRL1):c.26G>A (p.Trp9Ter)	Likely pathogenic
1700607	NM_014921.5(ADGRL1):c.1022A>G (p.Tyr341Cys)	Likely pathogenic
2582968	NM_014921.5(ADGRL1):c.1432C>T (p.Arg478Ter)	Likely pathogenic
2671964	NM_014921.5(ADGRL1):c.371_372dup (p.Gln125fs)	Likely pathogenic
3233337	NM_014921.5(ADGRL1):c.393C>A (p.Tyr131Ter)	Likely pathogenic
3258082	NM_014921.5(ADGRL1):c.1367_1383dup (p.Pro462fs)	Likely pathogenic
3258089	NM_014921.5(ADGRL1):c.70+2T>C	Likely pathogenic
3897576	NM_014921.5(ADGRL1):c.446_447del (p.His149fs)	Likely pathogenic
4085411	NM_014921.5(ADGRL1):c.1683C>G (p.Tyr561Ter)	Likely pathogenic
4293997	NM_014921.5(ADGRL1):c.245A>G (p.Gln82Arg)	Likely pathogenic
4687976	NM_014921.5(ADGRL1):c.3477_3480del (p.Phe1160fs)	Likely pathogenic
4689050	NM_014921.5(ADGRL1):c.2150-1G>C	Likely pathogenic
4795109	NM_014921.5(ADGRL1):c.812G>A (p.Gly271Glu)	Likely pathogenic
4821837	NM_014921.5(ADGRL1):c.342_343del (p.Cys115fs)	Likely pathogenic

SpliceAI

4051 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14151611:GTGCT:G	acceptor_gain	1.0000
19:14151612:TGCT:T	acceptor_gain	1.0000
19:14151613:GCT:G	acceptor_gain	1.0000
19:14151614:CT:C	acceptor_gain	1.0000
19:14151614:CTC:C	acceptor_gain	1.0000
19:14151615:TCT:T	acceptor_gain	1.0000
19:14151616:C:CC	acceptor_gain	1.0000
19:14152165:C:CT	acceptor_gain	1.0000
19:14152165:C:T	acceptor_gain	1.0000
19:14152166:A:T	acceptor_gain	1.0000
19:14152305:TCAC:T	donor_loss	1.0000
19:14152306:CACCT:C	donor_loss	1.0000
19:14152307:ACCTG:A	donor_loss	1.0000
19:14152308:CC:C	donor_loss	1.0000
19:14152434:GTAC:G	acceptor_loss	1.0000
19:14152439:T:A	acceptor_loss	1.0000
19:14152511:TCTCA:T	donor_loss	1.0000
19:14152512:CTCA:C	donor_loss	1.0000
19:14152513:TCA:T	donor_loss	1.0000
19:14152514:CA:C	donor_loss	1.0000
19:14152609:CGGCT:C	acceptor_gain	1.0000
19:14152612:CT:C	acceptor_gain	1.0000
19:14155357:A:C	donor_loss	1.0000
19:14155358:CCTT:C	donor_gain	1.0000
19:14156104:GCTCA:G	donor_loss	1.0000
19:14156105:CTCAC:C	donor_loss	1.0000
19:14156106:TCA:T	donor_loss	1.0000
19:14156107:CA:C	donor_loss	1.0000
19:14156108:A:AC	donor_gain	1.0000
19:14156108:ACTT:A	donor_loss	1.0000

AlphaMissense

9511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:14152593:C:A	W1153C	1.000
19:14152593:C:G	W1153C	1.000
19:14152595:A:G	W1153R	1.000
19:14152595:A:T	W1153R	1.000
19:14157412:C:G	G867R	1.000
19:14157927:G:C	C835W	1.000
19:14157928:C:T	C835Y	1.000
19:14157933:A:C	C833W	1.000
19:14157935:A:G	C833R	1.000
19:14157970:C:G	C821S	1.000
19:14157971:A:T	C821S	1.000
19:14157984:C:A	W816C	1.000
19:14157984:C:G	W816C	1.000
19:14158017:C:A	W805C	1.000
19:14158017:C:G	W805C	1.000
19:14158019:A:G	W805R	1.000
19:14158019:A:T	W805R	1.000
19:14158026:G:C	C802W	1.000
19:14158028:A:G	C802R	1.000
19:14159531:C:A	W636C	1.000
19:14159531:C:G	W636C	1.000
19:14159533:A:G	W636R	1.000
19:14159533:A:T	W636R	1.000
19:14160164:A:G	L588P	1.000
19:14160176:A:G	L584P	1.000
19:14160188:A:G	L580P	1.000
19:14160614:C:A	W536C	1.000
19:14160614:C:G	W536C	1.000
19:14160626:G:C	C532W	1.000
19:14160627:C:A	C532F	1.000

dbSNP variants (sampled 300 via entrez): RS1000095606 (19:14148310 G>A), RS1000162009 (19:14160523 C>A,G,T), RS1000163874 (19:14182242 ATTG>A), RS1000259042 (19:14160798 C>T), RS1000272514 (19:14154202 A>G), RS1000290096 (19:14186330 T>A,C), RS1000307635 (19:14177382 G>A,C), RS1000349347 (19:14165331 C>G), RS1000361456 (19:14167475 C>T), RS1000428893 (19:14148729 A>G), RS1000432974 (19:14186631 G>A), RS1000438346 (19:14154565 C>T), RS1000447463 (19:14154208 A>G), RS1000523934 (19:14170450 G>A), RS1000544674 (19:14205518 G>A)

Disease associations

OMIM: gene MIM:616416 | disease phenotypes: MIM:620065

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental delay, behavioral abnormalities, and neuropsychiatric disorders	Strong	Autosomal dominant

Mondo (5): intellectual disability (MONDO:0001071), attention deficit-hyperactivity disorder (MONDO:0007743), developmental delay, behavioral abnormalities, and neuropsychiatric disorders (MONDO:0859292), specific learning disability (MONDO:0016225), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Specific learning disability (Orphanet:211047), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000540	Hypermetropia
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0002360	Sleep disturbance
HP:0007018	Attention deficit hyperactivity disorder
HP:0025336	Delayed ability to sit
HP:0025502	Overweight
HP:0031936	Delayed ability to walk
HP:0032388	Periventricular nodular heterotopia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000661_3	Mortality in heart failure	1.000000e-06
GCST012488_12	L1-L4 bone mineral density x serum urate levels interaction	7.000000e-06
GCST012488_46	L1-L4 bone mineral density x serum urate levels interaction	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D000067559	Specific Learning Disorder	C10.597.606.150.550.700; C23.888.592.604.150.550.700; F03.625.374.188.700; F03.625.562.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Adhesion Class GPCRs

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
α-latrotoxin	Full agonist	9.8	pKd
LTX(N4C)	Full agonist	9.6	pKd
lasso D	Partial agonist	8.8	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	5
Estradiol	decreases expression, increases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
sulforaphane	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
entinostat	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylhexyl Phthalate	increases abundance, decreases methylation	1
Doxorubicin	affects response to substance	1
Lead	affects expression, affects splicing	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	PHASE4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory