Is C3 p.Arg1512Cys (c.4534C>T) pathogenic?

C3 p.Arg1512Cys (c.4534C>T) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-30). AlphaMissense: ambiguous (0.5636); Very rare (popmax 0.00167%, amr); Associated with C3 glomerulonephritis.

What condition is associated with C3 p.Arg1512Cys (c.4534C>T)?

C3 p.Arg1512Cys (c.4534C>T) is associated with C3 glomerulonephritis, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Arg1512Cys (c.4534C>T) in the general population?

C3 p.Arg1512Cys (c.4534C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C3 p.Arg1512Cys (c.4534C>T)?

AlphaMissense predicts ambiguous (score 0.5636) — an in-silico prediction, not a clinical call.

C3 p.Arg1512Cys

c.4534C>T · rs1408701335 · VCV1344660

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

C3 glomerulonephritis

Computational evidence

Protein change
AlphaMissense	0.5636	ambiguous
REVEL	0.292	indeterminate
SaProt	LLR -7.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 6,714 bp · p 0.081 · regional, not allelic
Overall
CADD	29.3	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 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000806% 13/1,613,180 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.00102%	98,272

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.Arg1512Cys
Coding: c.4534C>T
MANE Select: NM_000064
dbSNP: rs1408701335
Type: single nucleotide variant
Location: chr19:6679419 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1512: a β-strand; a disulfide bond

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

C3 glomerulonephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome with C3 anomaly

Similar variants

C3 p.Arg1512His 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 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-arg1512cys (accessed [today's date]).

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