ADGRL1

protein-coding

adhesion G protein-coupled receptor L1, the group of Adhesion G protein-coupled receptors, subfamily L

Gene summary

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.[provided by RefSeq, Oct 2008]

Previous symbols:

LPHN1

MANE transcript

NM_014921.5

Inheritance

ClinVar variants

P:40U:330B:64

Top phenotype

Developmental delay, behavioral abnormalities, and neuropsychiatric disorders6

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr19:14,147,743-14,206,187

External References & Databases

Ensembl (ENSG00000072071)

Transcript & Mutation Effects

hg38 • Region Span ~58.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, behavioral abnormalities, and neuropsychiatric disordersMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859292

Submitter: Ambry Genetics

developmental delay, behavioral abnormalities, and neuropsychiatric disordersSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859292

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*ADGRL1* encodes an adhesion G protein-coupled receptor, also known as latrophilin 1, which has been implicated in synaptic development, maturation, and activity. *ADGRL1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2022 (Vitobello et al., PMID: 35907405). Clinical features observed in affected individuals include developmental delay, variable intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, hypotonia, sleep disturbances, and mild facial dysmorphism. Less common findings include macrocephaly, overweight, joint hypermobility, and seizures. Thirteen variants (missense, nonsense, and frameshift) that have been reported in 8 probands in 1 publication (PMID: 35907405) and in 5 clinical laboratory submissions to ClinVar are included in this curation. In cases where parental testing was performed, the variants occurred *de novo*, except for 1 nonsense variant present in 2 affected siblings and inherited from the father with intellectual disability. *ADGRL1* is highly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.28, gnomAD v4.1.1) and missense variants (Z score = 5.05). The mechanism of pathogenicity is reported to be loss of function (PMID: 35907405). This gene-disease relationship is also supported by experiments in cultured neurons showing that Adgrl1 is essential for the assembly of inhibitory synapses (PMID: 38684366). In summary, there is definitive evidence to support the relationship between *ADGRL1* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 15, 2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Developmental delay, behavioral abnormalities, and neuropsychiatric disorders6AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 35907405

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADGRL1 variants in ClinVar

13 Conditions Cataloged

Inborn genetic diseasesTotal: 214

not providedTotal: 139

Developmental delay, behavioral abnormalities, and neuropsychiatric disordersTotal: 71

not specifiedTotal: 23

ADGRL1-related conditionTotal: 9

Global developmental delayTotal: 8

Attention deficit hyperactivity disorderTotal: 5

Autistic behaviorTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014921.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	43 clinvar	1 clinvar	46
missense	3 clinvar	4 clinvar	293 clinvar	20 clinvar		320
nonsense	5 clinvar	11 clinvar	6 clinvar			22
start loss						0
frameshift	7 clinvar	6 clinvar	16 clinvar			29
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	13 clinvar			17
Total	16	24	330	63	1	434

Highest pathogenic variant AF is 0.000003420726

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014921.5	RefSeq	NP_055736.2	22	MANE Select
ENST00000361434.8	Ensembl	ENSP00000355328.2	22	MANE Select
NM_001008701.3	RefSeq	NP_001008701.1	23	Standard
ENST00000340736.10	Ensembl	ENSP00000340688.5	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPCRs, Class B Secretin-like

Biological Process

heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
cell surface receptor signaling pathway
G protein-coupled receptor signaling pathway
adenylate cyclase-activating G protein-coupled receptor signaling pathway
calcium-mediated signaling using intracellular calcium source

Molecular Function

G protein-coupled receptor activity
protein binding
latrotoxin receptor activity
carbohydrate binding
cell adhesion molecule binding

Cellular Component

plasma membrane
integral component of plasma membrane
postsynaptic density
integral component of membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340736
Coding exons: 23
Length: 56250
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.43	640	935	0.685	0.0000651	9410
Missense (PolyPhen)		235	433.4	0.54222		4243
Synonymous	-1.72	470	425	1.11	0.0000323	3087
Loss of Function	6.99	7	70.3	0.0996	0.00000411	695

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000035	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.231

Intolerance Scores

RVIS EVS: -2.63
RVIS percentile EVS: 0.8

Essentials

Essential (gene trap): N