Is C3 p.Asp641Asn (c.1921G>A) pathogenic?

C3 p.Asp641Asn (c.1921G>A) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-05). AlphaMissense: ambiguous (0.5024); Very rare (popmax 0.00167%, amr); Associated with familial hemolytic anemia.

What condition is associated with C3 p.Asp641Asn (c.1921G>A)?

C3 p.Asp641Asn (c.1921G>A) is associated with familial hemolytic anemia (ClinVar).

How common is C3 p.Asp641Asn (c.1921G>A) in the general population?

C3 p.Asp641Asn (c.1921G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C3 p.Asp641Asn (c.1921G>A)?

AlphaMissense predicts ambiguous (score 0.5024) — an in-silico prediction, not a clinical call.

C3 p.Asp641Asn

c.1921G>A · rs1348311492 · VCV544828

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

familial hemolytic anemia

Computational evidence

Protein change
AlphaMissense	0.5024	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -11.16	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.0	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 0.00167% Admixed American · 1/60,014 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00123% 18/1,461,734 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	0.00136%	73,751
South Asian	0.0011%	91,084

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.Asp641Asn
Coding: c.1921G>A
MANE Select: NM_000064
dbSNP: rs1348311492
Type: single nucleotide variant
Location: chr19:6707854 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 641: an α-helix; a disulfide bond

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

Disease context

familial hemolytic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C3 p.Asp641= Conflicting classifications of pathogenicity ★ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same type
C3 c.2863+1G>T Likely pathogenic ★★ same type
C3 c.4030-2A>G Likely pathogenic ★★ same type
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same type
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ same type

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-asp641asn (accessed [today's date]).

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