Is C5AR2 p.Pro261Leu (c.782C>T) pathogenic?

C5AR2 p.Pro261Leu (c.782C>T) is classified Uncertain significance in C5AR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.4059); Very rare (popmax 0.00492%, nfe).

How common is C5AR2 p.Pro261Leu (c.782C>T) in the general population?

C5AR2 p.Pro261Leu (c.782C>T) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about C5AR2 p.Pro261Leu (c.782C>T)?

AlphaMissense predicts ambiguous (score 0.4059) — an in-silico prediction, not a clinical call.

C5AR2 p.Pro261Leu

c.782C>T · VCV3994121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4059	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -10.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.29, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 1,010 bp · p 0.66 · regional, not allelic
Overall
CADD	22.1	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 0.00492% European (non-Finnish) · 58/1,179,938 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00409% 66/1,613,598 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,344
Remaining individualsnot grpmax-eligible	0.0032%	31,234
African / African-American	0.00267%	37,477
South Asian	0.0022%	45,541
Admixed American	0.00167%	59,994
Finnishnot grpmax-eligible	0.00157%	63,672

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.Pro261Leu
Coding: c.782C>T
MANE Select: NM_001271749
Type: single nucleotide variant
Location: chr19:47341581 (GRCh38)
Gene constraint: LOEUF 1.788 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 86.24 · 7 PDB

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

Similar variants

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
C5AR2 p.Ala199Thr 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-pro261leu (accessed [today's date]).

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