Is C3 p.Pro174= (c.522G>A) pathogenic?

C3 p.Pro174= (c.522G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-09). Ultra-rare (popmax 0.012%, afr); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Pro174= (c.522G>A)?

C3 p.Pro174= (c.522G>A) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is C3 p.Pro174= (c.522G>A) in the general population?

C3 p.Pro174= (c.522G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

C3 p.Pro174=

c.522G>A · rs376520694 · VCV1712454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

atypical hemolytic-uremic syndrome

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 -1	GERP -3.5
Overall
CADD	7.045	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,940 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00211% 34/1,613,456 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,327
East Asian	0.00668%	14,963
Remaining individualsnot grpmax-eligible	0.0064%	15,620
South Asian	0.00439%	22,769
European (non-Finnish)	0.00119%	84,276

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.Pro174=
Coding: c.522G>A
MANE Select: NM_000064
dbSNP: rs376520694
Type: single nucleotide variant
Location: chr19:6714429 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 174: a β-strand

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

Disease context

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

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

C3 p.Pro174Leu Uncertain significance ★ ⚠ same residue
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.Ile1157Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Trp1034Arg Likely pathogenic ★★ same condition
C3 c.1269+4C>A Uncertain significance ★★ same condition
C3 c.-44C>T Uncertain significance ★★ 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-pro174 (accessed [today's date]).

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