CALCRL

protein-coding

calcitonin receptor like receptor, the group of Calcitonin receptors

Gene summary

Enables adrenomedullin binding activity; adrenomedullin receptor activity; and calcitonin gene-related peptide receptor activity. Involved in several processes, including G protein-coupled receptor signaling pathway; cellular response to sucrose stimulus; and receptor internalization. Located in several cellular components, including endoplasmic reticulum; endosome; and lysosome. Part of CGRP receptor complex and adrenomedullin receptor complex. Implicated in hereditary lymphedema. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_005795.6

Inheritance

ClinVar variants

U:31B:5

Top phenotype

Lymphatic malformation 8

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr2:187,341,964-187,448,460

External References & Databases

Ensembl (ENSG00000064989)

Transcript & Mutation Effects

hg38 • Region Span ~106.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphatic malformation 8LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032907

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lymphatic malformation 8AR

Manifestation: Cardiovascular

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: 30115739

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CALCRL variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 34

not providedTotal: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Lymphatic malformation 8Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005795.6. 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			1 clinvar	1 clinvar	1 clinvar	3
missense			29 clinvar	2 clinvar	1 clinvar	32
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	31	3	2	36

Highest pathogenic variant AF is 6.862504e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005795.6	RefSeq	NP_005786.1	12	MANE Select
ENST00000392370.8	Ensembl	ENSP00000376177.3	12	MANE Select
NM_001271751.2	RefSeq	NP_001258680.1	12	Standard
NM_001369434.1	RefSeq	NP_001356363.1	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
calcrla	Danio rerio	Structure: trunk vasculature Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

calcrla

Danio rerio

Structure: trunk vasculature

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vascular smooth muscle contraction - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Endothelin Pathways
GPCRs, Class B Secretin-like
Signaling by GPCR

Biological Process

angiogenesis
calcium ion transport
cell surface receptor signaling pathway
G protein-coupled receptor signaling pathway
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger

Molecular Function

adrenomedullin receptor activity
calcitonin gene-related peptide receptor activity
G protein-coupled receptor activity
calcitonin receptor activity
protein binding

Cellular Component

cytoplasm
lysosome
endosome
endoplasmic reticulum
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409998
Coding exons: 12
Length: 105332
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125711
p: 0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.09	144	234	0.615	0.0000110	3047
Missense (PolyPhen)		28	62.721	0.44642		870
Synonymous	0.626	76	83.3	0.913	0.00000433	812
Loss of Function	4.18	3	26.0	0.115	0.00000118	326

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. {ECO:0000250, ECO:0000269|PubMed:22102369}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.401
RVIS EVS: 0.17
RVIS percentile EVS: 65.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.774

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium