Is C3 p.Pro933= (c.2799G>A) pathogenic?

C3 p.Pro933= (c.2799G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-23). Rare (popmax 0.231%, mid); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Pro933= (c.2799G>A)?

C3 p.Pro933= (c.2799G>A) 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.Pro933= (c.2799G>A) in the general population?

C3 p.Pro933= (c.2799G>A) is rare (popmax 0.231%, mid) (gnomAD).

C3 p.Pro933=

c.2799G>A · rs149209011 · VCV330299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.231%, mid)

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.80	acceptor gain · deltas
Pangolin	Δ0.41	gain · loss 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -15	GERP -3.2
Overall
CADD	12.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.231% Middle Eastern · 14/6,062 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00954% 154/1,613,848 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.231%	433
African / African-American	0.0934%	1,071
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Admixed American	0.0167%	5,999
European (non-Finnish)	0.0039%	25,649
East Asian	0.00223%	44,864

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.Pro933=
Coding: c.2799G>A
MANE Select: NM_000064
dbSNP: rs149209011
Type: single nucleotide variant
Location: chr19:6696657 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 933: 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

Similar variants

C3 p.Pro933Leu 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
C3 p.Arg764Ter Pathogenic/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-pro933 (accessed [today's date]).

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