Is C5AR2 p.Pro168Thr (c.502C>A) pathogenic?

C5AR2 p.Pro168Thr (c.502C>A) is classified Uncertain significance in C5AR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.7244); Very rare (popmax 0.000254%, nfe).

How common is C5AR2 p.Pro168Thr (c.502C>A) in the general population?

C5AR2 p.Pro168Thr (c.502C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about C5AR2 p.Pro168Thr (c.502C>A)?

AlphaMissense predicts likely pathogenic (score 0.7244) — an in-silico prediction, not a clinical call.

C5AR2 p.Pro168Thr

c.502C>A · VCV3994127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7244	likely pathogenic · top 10% in C5AR2
REVEL	0.239	benign-leaning
SaProt	LLR -15.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,010 bp · p 0.66 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,890 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,608,674 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C5AR2
Protein: p.Pro168Thr
Coding: c.502C>A
MANE Select: NM_001271749
Type: single nucleotide variant
Location: chr19:47341301 (GRCh38)
Gene constraint: LOEUF 1.788 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 7 PDB
Residue 168: a disulfide bond

Full C5AR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C5AR2 p.Pro168Leu Uncertain significance ★ ⚠ same residue
C5AR2 p.Ile171Thr Uncertain significance ★★ ⚠ same type
C5AR2 p.His329Arg Benign ★★ same type
C5AR2 p.Leu281= Benign ★★ same type
C5AR2 p.Leu299Val Benign/Likely benign ★★ ⚠ same type
C5AR2 p.Ser17= Benign ★★ same type
C5AR2 p.Ala136Thr Uncertain significance ★ ⚠ same type
C5AR2 p.Ala170Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c5ar2-p-pro168thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown