Is C3 p.Arg1320= (c.3958C>A) pathogenic?

C3 p.Arg1320= (c.3958C>A) is classified Benign/Likely benign in C3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-24). Low-frequency (popmax 1.23%, afr); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Arg1320= (c.3958C>A)?

C3 p.Arg1320= (c.3958C>A) is associated with atypical hemolytic-uremic syndrome with C3 anomaly, age related macular degeneration 9, complement component 3 deficiency (ClinVar).

How common is C3 p.Arg1320= (c.3958C>A) in the general population?

C3 p.Arg1320= (c.3958C>A) is low-frequency (popmax 1.23%, afr) (gnomAD).

C3 p.Arg1320=

c.3958C>A · rs141718696 · VCV724798

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.23%, afr)

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.9, phastCons 0.96
Overall
CADD	9.287	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.23% African / African-American · 926/75,008 alleles

Filtering AF 1.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.14%

Overall 0.0645% 1,041/1,613,678 alleles · low-frequency exomes 505/1,461,446 · genomes 536/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.23%	81
Remaining individualsnot grpmax-eligible	0.0864%	1,157
Admixed American	0.085%	1,177
Middle Eastern	0.0175%	5,712
South Asian	0.00549%	18,210
European (non-Finnish)	0.000339%	295,004

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.Arg1320=
Coding: c.3958C>A
MANE Select: NM_000064
dbSNP: rs141718696
Type: single nucleotide variant
Location: chr19:6684999 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1320: a functional site (cleavage; by factor i); a β-strand

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: age related macular degeneration 9 complement component 3 deficiency

Similar variants

C3 p.Arg1320Ter Pathogenic ★ same residue
C3 p.Arg1320Gln Uncertain significance ★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G 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

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-arg1320 (accessed [today's date]).

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