Is C3 p.Arg478Leu (c.1433G>T) pathogenic?

C3 p.Arg478Leu (c.1433G>T) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-30). AlphaMissense: ambiguous (0.4158); Very rare (popmax 0.00333%, amr); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Arg478Leu (c.1433G>T)?

C3 p.Arg478Leu (c.1433G>T) 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.Arg478Leu (c.1433G>T) in the general population?

C3 p.Arg478Leu (c.1433G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C3 p.Arg478Leu (c.1433G>T)?

AlphaMissense predicts ambiguous (score 0.4158) — an in-silico prediction, not a clinical call.

C3 p.Arg478Leu

c.1433G>T · rs747968673 · VCV633671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4158 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.4158	ambiguous
REVEL	0.355	indeterminate
SaProt	LLR -8.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 0.38, phastCons 0.9
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,999
European (non-Finnish)	0.00144%	69,413

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.Arg478Leu
Coding: c.1433G>T
MANE Select: NM_000064
dbSNP: rs747968673
Type: single nucleotide variant
Location: chr19:6711033 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 478: a β-strand

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

C3 p.Arg478Ter Pathogenic ★ same residue
C3 p.Arg478Gln 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

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-arg478leu (accessed [today's date]).

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