Is C3 p.Pro890Arg (c.2669C>G) pathogenic?

C3 p.Pro890Arg (c.2669C>G) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-05). AlphaMissense: likely benign (0.1729); Very rare (popmax 0.00802%, afr).

How common is C3 p.Pro890Arg (c.2669C>G) in the general population?

C3 p.Pro890Arg (c.2669C>G) is very rare (popmax 0.00802%, afr) (gnomAD).

What do computational predictors say about C3 p.Pro890Arg (c.2669C>G)?

AlphaMissense predicts likely benign (score 0.1729) — an in-silico prediction, not a clinical call.

C3 p.Pro890Arg

c.2669C>G · rs753876258 · VCV1502901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00802%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1729	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	12.01	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 0.00802% African / African-American · 6/74,830 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00136% 22/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00802%	12,472
East Asian	0.00668%	14,962
Admixed American	0.00334%	29,982
European (non-Finnish)	0.000932%	107,272

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: C3
Protein: p.Pro890Arg
Coding: c.2669C>G
MANE Select: NM_000064
dbSNP: rs753876258
Type: single nucleotide variant
Location: chr19:6697471 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 890: a disulfide bond

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C3 p.Pro890His Uncertain significance ★★ ⚠ same residue
C3 p.Pro890Ser Uncertain significance ★★ ⚠ same residue
C3 p.Pro890Leu Uncertain significance ★ ⚠ same residue
C3 p.Pro890= Likely benign ★ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same type
C3 c.2863+1G>T Likely pathogenic ★★ same type
C3 c.4030-2A>G Likely pathogenic ★★ same type
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ 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/c3-p-pro890arg (accessed [today's date]).

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