C5AR2

Chr 19

complement C5a receptor 2

Also known as: C5L2, GPF77, GPR77

NCBI Gene: 27202 ENSG00000134830 UniProt: Q9P296 OMIM: 609949

The C5AR2 protein is a G-protein coupled receptor that binds complement anaphylatoxins (C5a, C3a, C4a) and their dearginated forms, functioning as part of the innate immune system's complement cascade. Unlike typical GPCRs, it does not associate with intracellular G-proteins and may act as a decoy receptor or signal through beta-arrestin pathways to modulate inflammatory responses. No pediatric neurogenetic disorders have been definitively associated with C5AR2 mutations in the provided data.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a G-protein coupled receptor 1 family member involved in the complement system of the innate immune response. Unlike classical G-protein coupled receptors, the encoded protein does not associate with intracellular G-proteins. It may instead modulate signal transduction through the beta-arrestin pathway, and may alternatively act as a decoy receptor. This gene may be involved in coronary artery disease and in the pathogenesis of sepsis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.35

Clinical Summary— C5AR2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

73 VUS of 90 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.35LOEUF

pLI 0.246

Z-score 1.19

OE 0.30 (0.10–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.15Z-score

OE missense 1.03 (0.92–1.15)

214 obs / 208.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.30 (0.10–1.35)

0≤0.351.4

Missense OE?1.03 (0.92–1.15)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 1 / 3.4Missense obs/exp: 214 / 208.1Syn Z: -0.73

This gene — mechanism propensity

0.6937th %ile

GOF

0.73top 25%

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-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

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.

ClinVar Variant Classifications

90 submitted variants in ClinVar

ClinVar

Classification Summary

VUS73

Likely Benign10

Benign4

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	73	0	0	73
Likely Benign	0	7	0	3	10
Benign	0	2	0	2	4
Conflicting	—				1
Total	0	82	0	5	88

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap C5AR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →