CALCRL

Chr 2AR

calcitonin receptor like receptor

Also known as: CGRPR, CRLR, LMPHM8

NCBI Gene: 10203 ENSG00000064989 UniProt: Q16602 OMIM: 114190

The protein functions as a G protein-coupled receptor that forms complexes with receptor-activity-modifying proteins (RAMPs) to bind calcitonin gene-related peptide and adrenomedullin, activating cAMP-dependent signaling pathways. Mutations cause lymphatic malformation with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants, indicating critical importance for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.301 OMIM phenotype

Clinical Summary— CALCRL

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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.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 29 VUS of 46 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.12 (0.05–0.30)

0≤0.351.4

Missense OE?0.62 (0.54–0.71)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 3 / 26.0Missense obs/exp: 144 / 234.1Syn Z: 0.63

This gene — mechanism propensity

0.6649th %ile

GOF

0.77top 25%

LOF

0.3940th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

LOFLOEUF 0.30

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

46 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS29

Likely Benign3

Benign4

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	1
Likely Pathogenic	0	0	0	0
VUS	29	0	0	29
Likely Benign	2	1	0	3
Benign	1	2	1	4
Total	33	3	1	37

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap CALCRL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →