Is C3 p.Arg1491Gln (c.4472G>A) pathogenic?

C3 p.Arg1491Gln (c.4472G>A) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0722); Very rare (popmax 0.005%, amr).

How common is C3 p.Arg1491Gln (c.4472G>A) in the general population?

C3 p.Arg1491Gln (c.4472G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about C3 p.Arg1491Gln (c.4472G>A)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

C3 p.Arg1491Gln

c.4472G>A · rs775654009 · VCV2160017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.5
Regional constraint	o/e 0.91	unconstrained · MANE · 6,714 bp · p 0.081 · regional, not allelic
Overall
CADD	4.744	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00279% 45/1,612,816 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
South Asian	0.00329%	30,353
Remaining individualsnot grpmax-eligible	0.0032%	31,215
European (non-Finnish)	0.00305%	32,748

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.Arg1491Gln
Coding: c.4472G>A
MANE Select: NM_000064
dbSNP: rs775654009
Type: single nucleotide variant
Location: chr19:6679481 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1491: a β-strand; a disulfide bond

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

Similar variants

C3 p.Arg1491Trp Conflicting classifications of pathogenicity ★ ⚠ 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
C3 p.Arg764Ter Pathogenic/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-arg1491gln (accessed [today's date]).

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