Is C3 p.Val564= (c.1692G>A) pathogenic?

C3 p.Val564= (c.1692G>A) is classified Benign/Likely benign in C3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 52.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Val564= (c.1692G>A)?

C3 p.Val564= (c.1692G>A) is associated with atypical hemolytic-uremic syndrome with C3 anomaly, age related macular degeneration 9, complement component 3 deficiency (ClinVar).

C3 p.Val564=

Q: How common is C3 p.Val564= (c.1692G>A) in the general population?

C3 p.Val564= (c.1692G>A) is common (popmax 52.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1692G>A · rs2230204 · VCV330321

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 52.7%, afr) — too common for a highly-penetrant pathogenic allele

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 0.38	GERP -0.78, phastCons 0.99
Overall
CADD	8.031	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.7% African / African-American · 39,376/74,736 alleles

Filtering AF 52.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.1%

Overall 31.8% 513,525/1,612,958 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	52.7%	2
East Asian	47.7%	2
South Asian	44%	2
Admixed American	38.8%	3
Remaining individualsnot grpmax-eligible	32.2%	3
Finnishnot grpmax-eligible	30.7%	3
Ashkenazi Jewishnot grpmax-eligible	29.9%	3
European (non-Finnish)	28.7%	3
Middle Eastern	25.2%	4
Amishnot grpmax-eligible	21.5%	5

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.Val564=
Coding: c.1692G>A
MANE Select: NM_000064
dbSNP: rs2230204
Type: single nucleotide variant
Location: chr19:6709837 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 564: a β-strand; 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 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
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-val564 (accessed [today's date]).

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