Is C3 p.Thr1331= (c.3993A>G) pathogenic?

C3 p.Thr1331= (c.3993A>G) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0516%, sas); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Thr1331= (c.3993A>G)?

C3 p.Thr1331= (c.3993A>G) 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.Thr1331= (c.3993A>G) in the general population?

C3 p.Thr1331= (c.3993A>G) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

C3 p.Thr1331=

c.3993A>G · rs202210310 · VCV330289

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

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 -6.3	GERP -3.5
Overall
CADD	1.285	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% South Asian · 47/91,088 alleles

Filtering AF 0.0398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00533% 86/1,614,216 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,938
Remaining individualsnot grpmax-eligible	0.0368%	2,718
East Asian	0.0245%	4,081
Admixed American	0.005%	20,009
African / African-American	0.00133%	75,052
European (non-Finnish)	8.47e-05%	1,180,027

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.Thr1331=
Coding: c.3993A>G
MANE Select: NM_000064
dbSNP: rs202210310
Type: single nucleotide variant
Location: chr19:6684811 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1331: a β-strand; a disulfide bond

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 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
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ same condition
C3 c.683-3C>A Uncertain significance ★★ 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-thr1331 (accessed [today's date]).

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