Is C3 p.Glu689= (c.2067G>A) pathogenic?

C3 p.Glu689= (c.2067G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-01). Rare (popmax 0.187%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Glu689= (c.2067G>A)?

C3 p.Glu689= (c.2067G>A) is associated with atypical hemolytic-uremic syndrome, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Glu689= (c.2067G>A) in the general population?

C3 p.Glu689= (c.2067G>A) is rare (popmax 0.187%, nfe) (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.Glu689=

c.2067G>A · rs147477257 · VCV330312

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.187%, nfe)

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 -0.18	GERP -1.8
Overall
CADD	3.888	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.187% European (non-Finnish) · 2,202/1,179,052 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.143% 2,309/1,611,634 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.187%	535
Remaining individualsnot grpmax-eligible	0.0833%	1,200
Finnishnot grpmax-eligible	0.0409%	2,448
African / African-American	0.0361%	2,769
Admixed American	0.00335%	29,819

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.Glu689=
Coding: c.2067G>A
MANE Select: NM_000064
dbSNP: rs147477257
Type: single nucleotide variant
Location: chr19:6707254 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 689: an α-helix; a disulfide bond

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

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

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

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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
C3 p.Ile1157Thr 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-glu689 (accessed [today's date]).

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