Is C3 p.Asn451Ser (c.1352A>G) pathogenic?

C3 p.Asn451Ser (c.1352A>G) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.00446%, eas); Associated with atypical hemolytic-uremic syndrome with C3 anomaly.

What condition is associated with C3 p.Asn451Ser (c.1352A>G)?

C3 p.Asn451Ser (c.1352A>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.Asn451Ser (c.1352A>G) in the general population?

C3 p.Asn451Ser (c.1352A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about C3 p.Asn451Ser (c.1352A>G)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

C3 p.Asn451Ser

c.1352A>G · VCV3584170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with C3 anomaly

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.83	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 0.21	GERP -0.75, phastCons 0.015
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	16.51	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000992% 16/1,613,712 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
South Asian	0.00329%	30,356
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000847%	117,995

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.Asn451Ser
Coding: c.1352A>G
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6711114 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 451: an α-helix

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-asn451ser (accessed [today's date]).

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