Is C3 p.Arg161Trp (c.481C>T) pathogenic?

C3 p.Arg161Trp (c.481C>T) is classified Pathogenic/Likely pathogenic in C3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-30). AlphaMissense: likely benign (0.1851); Very rare (popmax 0.000424%, nfe); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Arg161Trp (c.481C>T)?

C3 p.Arg161Trp (c.481C>T) is associated with atypical hemolytic-uremic syndrome with C3 anomaly, C3 glomerulonephritis, atypical hemolytic-uremic syndrome (ClinVar).

How common is C3 p.Arg161Trp (c.481C>T) in the general population?

C3 p.Arg161Trp (c.481C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about C3 p.Arg161Trp (c.481C>T)?

AlphaMissense predicts likely benign (score 0.1851) — an in-silico prediction, not a clinical call.

C3 p.Arg161Trp

c.481C>T · rs776423109 · VCV1163121

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
AlphaMissense	0.1851	likely benign ⚠ discordant with ClinVar
REVEL	0.53	indeterminate
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.55, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	23.5	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 0.000424% European (non-Finnish) · 5/1,180,006 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,870 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.Arg161Trp
Coding: c.481C>T
MANE Select: NM_000064
dbSNP: rs776423109
Type: single nucleotide variant
Location: chr19:6718117 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB

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

Disease context

atypical hemolytic-uremic syndrome with C3 anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: C3 glomerulonephritis atypical hemolytic-uremic syndrome

Similar variants

C3 p.Arg161Gly Uncertain significance ★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T 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 p.Ile1157Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Trp1034Arg 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-arg161trp (accessed [today's date]).

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