Is C3 p.Ser562= (c.1686G>A) pathogenic?

C3 p.Ser562= (c.1686G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-06). Ultra-rare (popmax 0.0254%, afr); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Ser562= (c.1686G>A)?

C3 p.Ser562= (c.1686G>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.Ser562= (c.1686G>A) in the general population?

C3 p.Ser562= (c.1686G>A) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

C3 p.Ser562=

c.1686G>A · rs143750180 · VCV1430457

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, 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 -0.27	GERP -0.69, phastCons 0.17
Overall
CADD	12.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,810 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00211% 34/1,611,648 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,937
Finnishnot grpmax-eligible	0.0127%	7,897
East Asian	0.00223%	44,852
Admixed American	0.00167%	59,894
South Asian	0.0011%	90,994
European (non-Finnish)	0.000339%	294,759

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.Ser562=
Coding: c.1686G>A
MANE Select: NM_000064
dbSNP: rs143750180
Type: single nucleotide variant
Location: chr19:6710639 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 562: 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.Ser562Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser562 (accessed [today's date]).

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