Is C3 p.Ser1343= (c.4029G>A) pathogenic?

C3 p.Ser1343= (c.4029G>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-22). Very rare (popmax 0.008%, afr); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Ser1343= (c.4029G>A)?

C3 p.Ser1343= (c.4029G>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.Ser1343= (c.4029G>A) in the general population?

C3 p.Ser1343= (c.4029G>A) is very rare (popmax 0.008%, afr) (gnomAD).

C3 p.Ser1343=

c.4029G>A · rs190354796 · VCV1002458

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.008%, 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
Pangolin	Δ0.59	loss · gain 0.14 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.008% African / African-American · 6/75,034 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00105% 17/1,614,134 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,506
South Asian	0.00659%	15,181
East Asian	0.00446%	22,440
European (non-Finnish)	0.000254%	393,331

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.Ser1343=
Coding: c.4029G>A
MANE Select: NM_000064
dbSNP: rs190354796
Type: single nucleotide variant
Location: chr19:6684775 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1343: 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

Similar variants

C3 p.Ser1343Leu 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-ser1343 (accessed [today's date]).

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