Is C3 p.Arg748= (c.2244G>A) pathogenic?

C3 p.Arg748= (c.2244G>A) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). Very rare (popmax 0.00224%, eas); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Arg748= (c.2244G>A)?

C3 p.Arg748= (c.2244G>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.Arg748= (c.2244G>A) in the general population?

C3 p.Arg748= (c.2244G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

C3 p.Arg748=

c.2244G>A · VCV3584136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

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 0.16	GERP -3.5, phastCons 0.078
Overall
CADD	12.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,730 alleles

Overall 6.21e-05% 1/1,609,556 alleles · very rare exomes 0/1,458,206 · genomes 1/151,350 · joint denominator

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.Arg748=
Coding: c.2244G>A
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6707077 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 748: a functional site (cleavage; by carboxypeptidases); a functional site (cleavage; by c3 convertase)

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 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 c.683-3C>A 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-arg748 (accessed [today's date]).

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