CALCRL

Chr 2AR

calcitonin receptor like receptor

Also known as: CGRPR, CRLR, LMPHM8

NCBI Gene: 10203ENSG00000064989UniProt: Q16602

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]

Primary Disease Associations & Inheritance

?Lymphatic malformation 8MIM #618773
AR
79
ClinVar variants
28
Pathogenic / LP
0.99
pLI score· haploinsufficient
5
Active trials
Clinical Summary— CALCRL
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 34 VUS of 79 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.30LOEUF
pLI 0.985
Z-score 4.18
OE 0.12 (0.05–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.09Z-score
OE missense 0.62 (0.54–0.71)
144 obs / 234.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.05–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.54–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91
0≤1.21.6
LoF obs/exp: 3 / 26.0Missense obs/exp: 144 / 234.1Syn Z: 0.63

ClinVar Variant Classifications

79 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic1
VUS34
Likely Benign4
Benign4
27
Pathogenic
1
Likely Pathogenic
34
VUS
4
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
27
0
27
Likely Pathogenic
0
0
1
0
1
VUS
0
29
5
0
34
Likely Benign
0
2
2
0
4
Benign
0
1
2
1
4
Total03237170

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CALCRL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Lymphatic malformation 8

MIM #618773

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CALCRL induces resistance to daunorubicin in acute myeloid leukemia cells through upregulation of XRCC5/TYK2/JAK1 pathway.
Tang S et al.·Anticancer Drugs
2024
miR-101-3p overexpression suppresses NSCLC progression through Immune-Related gene CALCRL regulation and lncRNA NEAT1 axis.
Tabassum G et al.·Mol Biol Rep
2025
Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-Analysis.
Liang YJ et al.·JAMA Ophthalmol
2024Meta-analysis
The Clinical Relevance and Prognostic Significance of Calcitonin Receptor-Like (CALCRL) Gene Expression in AML Patients.
Khorshied MM et al.·Asian Pac J Cancer Prev
2026Cohort
Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro.
Selvarajan I et al.·Arterioscler Thromb Vasc Biol
2024
CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia.
Gluexam T et al.·Int J Mol Sci
2019
Genome-Wide Pleiotropy Analysis Identifies Shared and Opposing Pathways Influencing Coronary Artery Disease and Cancer.
Yarmolinsky J et al.·Arterioscler Thromb Vasc Biol
2025
Integration of single-cell and bulk transcriptomics reveals immune-related signatures in keloid.
Wang H et al.·J Cosmet Dermatol
2023
Adrenomedullin signaling pathway polymorphisms and adverse pregnancy outcomes.
Lenhart PM et al.·Am J Perinatol
2014
Identifying a novel 5-gene signature predicting clinical outcomes in acute myeloid leukemia.
Sha K et al.·Clin Transl Oncol
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Vestibular MigraineDizzinessVertigo

Chinese Real-world Study of Treatment of Vestibular Migraine

NOT YET RECRUITING
NCT07203248Second Affiliated Hospital, School of Medicine, Zhejiang UniversityStarted 2025-12
CGRP R Inhibitor; CGRP Inhibitornone-CGRP
Healthy Volunteer

A Study to Compare Blood Levels of Different Dosage Formulations of the Study Medicine That Is a CGRP Receptor Antagonist in Healthy Adults

RECRUITING
NCT07261371Phase PHASE1PfizerStarted 2025-11-24
Test formulation (Treatment A)Reference formulation (Treatment B)Test formulation (Treatment C)
Episodic MigraineChronic MigraineMedication Overuse Headache

i-NEED: NEw migrainE Drugs Database

RECRUITING
NCT07103694IRCCS San Raffaele RomaStarted 2022-03-24
anti-CGRP monoclonal antibodiesgepantscombination of sumatriptan and naproxen
MigraineEpisodic MigraineChronic Migraine, Headache

Real-world Prospective Study on the Use of Anti-CGRP Drugs in Migraine

RECRUITING
NCT07159750Hospital Universitari Vall d'Hebron Research InstituteStarted 2024-01-02
CGRP antibody or gepant
Headache (Migraine)MigraineMigraine Headache

Molecular Phenotyping of Migraine Patients According to Sex and Age Through CGRP Quantification

RECRUITING
NCT06674772Hospital Universitari Vall d'Hebron Research InstituteStarted 2022-11-29
Saliva test

External Resources

Links to major genomics databases and tools