Is C3 p.Arg1393Pro (c.4178G>C) pathogenic?

C3 p.Arg1393Pro (c.4178G>C) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-22). AlphaMissense: likely pathogenic (0.6474); Very rare (popmax 0.0011%, sas).

How common is C3 p.Arg1393Pro (c.4178G>C) in the general population?

C3 p.Arg1393Pro (c.4178G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about C3 p.Arg1393Pro (c.4178G>C)?

AlphaMissense predicts likely pathogenic (score 0.6474) — an in-silico prediction, not a clinical call.

C3 p.Arg1393Pro

c.4178G>C · rs575119407 · VCV2831060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6474	likely pathogenic
REVEL	0.079	moderately benign-leaning
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.48, phastCons 0.55
Regional constraint	o/e 0.91	unconstrained · MANE · 6,714 bp · p 0.081 · regional, not allelic
Overall
CADD	22.5	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 0.0011% South Asian · 1/91,018 alleles

Overall 6.85e-05% 1/1,459,870 alleles · very rare

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.Arg1393Pro
Coding: c.4178G>C
MANE Select: NM_000064
dbSNP: rs575119407
Type: single nucleotide variant
Location: chr19:6682224 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1393: a disulfide bond

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

Similar variants

C3 p.Arg1393Gln Uncertain significance ★★ ⚠ same residue
C3 p.Arg1393Trp Uncertain significance ★★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same type
C3 c.2863+1G>T Likely pathogenic ★★ same type
C3 c.4030-2A>G Likely pathogenic ★★ same type
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same type

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-arg1393pro (accessed [today's date]).

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