Is C3 p.Pro577= (c.1731T>C) pathogenic?

C3 p.Pro577= (c.1731T>C) is classified Likely benign in C3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-01). Rare (popmax 0.143%, afr); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Pro577= (c.1731T>C)?

C3 p.Pro577= (c.1731T>C) is associated with atypical hemolytic-uremic syndrome with C3 anomaly, age related macular degeneration 9, complement component 3 deficiency (ClinVar).

How common is C3 p.Pro577= (c.1731T>C) in the general population?

C3 p.Pro577= (c.1731T>C) is rare (popmax 0.143%, afr) (gnomAD).

C3 p.Pro577=

c.1731T>C · rs148182019 · VCV1147883

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.143%, afr)

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -2.8
Overall
CADD	0.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.143% African / African-American · 107/75,006 alleles

Filtering AF 0.121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.00744% 120/1,613,974 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.143%	701
Admixed American	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	8.47e-05%	1,180,026

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.Pro577=
Coding: c.1731T>C
MANE Select: NM_000064
dbSNP: rs148182019
Type: single nucleotide variant
Location: chr19:6709798 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 577: a disulfide bond

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

Disease context

atypical hemolytic-uremic syndrome with C3 anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 complement component 3 deficiency C3 glomerulonephritis atypical hemolytic-uremic syndrome

Similar variants

C3 p.Pro577Leu Uncertain significance ★ ⚠ same residue
C3 p.Pro577Ser Uncertain significance ★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G Likely pathogenic ★★ same condition
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition

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-pro577 (accessed [today's date]).

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