Is C3 p.Asp549Asn (c.1645G>A) pathogenic?

C3 p.Asp549Asn (c.1645G>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.8556); Very rare (popmax 0.000339%, nfe); Associated with complement component 3 deficiency.

What condition is associated with C3 p.Asp549Asn (c.1645G>A)?

C3 p.Asp549Asn (c.1645G>A) is associated with complement component 3 deficiency, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Asp549Asn (c.1645G>A) in the general population?

C3 p.Asp549Asn (c.1645G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Complement component 3 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C3 p.Asp549Asn (c.1645G>A)?

AlphaMissense predicts likely pathogenic (score 0.8556) — an in-silico prediction, not a clinical call.

C3 p.Asp549Asn

c.1645G>A · rs1449441916 · VCV2736765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

complement component 3 deficiency

Computational evidence

Protein change
AlphaMissense	0.8556	likely pathogenic
REVEL	0.516	indeterminate
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	25.0	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 0.000339% European (non-Finnish) · 4/1,179,886 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,126 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00158%	63,470
European (non-Finnish)grpmax	0.000339%	294,971

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp549Asn
Coding: c.1645G>A
MANE Select: NM_000064
dbSNP: rs1449441916
Type: single nucleotide variant
Location: chr19:6710680 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 549: a β-strand; a UniProt-annotated variant site (in c3d; impairs secretion; variant confirmed at protein level)

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

Disease context

complement component 3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome with C3 anomaly

For Complement component 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

C3 p.Asp549= Likely benign ★ 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
C3 p.Arg764Ter Pathogenic/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-asp549asn (accessed [today's date]).

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