Is C3 p.Arg481Cys (c.1441C>T) pathogenic?

C3 p.Arg481Cys (c.1441C>T) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). AlphaMissense: ambiguous (0.3672); Very rare (popmax 0.00439%, sas).

How common is C3 p.Arg481Cys (c.1441C>T) in the general population?

C3 p.Arg481Cys (c.1441C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about C3 p.Arg481Cys (c.1441C>T)?

AlphaMissense predicts ambiguous (score 0.3672) — an in-silico prediction, not a clinical call.

C3 p.Arg481Cys

c.1441C>T · VCV3616444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3672	ambiguous
REVEL	0.116	moderately benign-leaning
SaProt	LLR -12.66	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.87	GERP -2.5
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	12.48	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 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000889% 13/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	0.000763%	131,113

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.Arg481Cys
Coding: c.1441C>T
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6711025 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 481: a turn

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

Similar variants

C3 p.Arg481Pro Uncertain significance ★ ⚠ same residue
C3 p.Arg481= Likely benign ★ 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-arg481cys (accessed [today's date]).

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