Is C3 p.Arg102Gly (c.304C>G) pathogenic?

C3 p.Arg102Gly (c.304C>G) is classified Benign/Likely benign in C3 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0748); Common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Arg102Gly (c.304C>G)?

C3 p.Arg102Gly (c.304C>G) is associated with atypical hemolytic-uremic syndrome, age related macular degeneration 9, complement component 3 deficiency (ClinVar).

How is Atypical hemolytic uremic syndrome inherited?

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

What do computational predictors say about C3 p.Arg102Gly (c.304C>G)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

C3 p.Arg102Gly

Q: How common is C3 p.Arg102Gly (c.304C>G) in the general population?

C3 p.Arg102Gly (c.304C>G) is common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.304C>G · rs2230199 · VCV17056

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 21.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.28	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 0.27	GERP 0.97
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	9.935	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 21.3% European (non-Finnish) · 251,702/1,179,934 alleles

Filtering AF 21.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.2%

Overall 18.7% 302,553/1,614,024 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	21.3%	5
Ashkenazi Jewishnot grpmax-eligible	20.9%	5
Remaining individualsnot grpmax-eligible	18.3%	5
Finnishnot grpmax-eligible	18%	6
Middle Eastern	15.6%	6
South Asian	12.9%	8
Admixed American	9.21%	11
Amishnot grpmax-eligible	6.47%	15
African / African-American	4.37%	23
East Asian	0.0691%	1,448

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.Arg102Gly
Coding: c.304C>G
MANE Select: NM_000064
dbSNP: rs2230199
Type: single nucleotide variant
Location: chr19:6718376 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 102: a UniProt-annotated variant site (in allele c3f; risk factor for armd9; results in decreased binding affinity for regulator factor h; results in reduced sensitivity to cleavage by factor i)

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 complement component 3 deficiency C3 glomerulonephritis focal segmental glomerulosclerosis

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

C3 p.Arg102His 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
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-arg102gly (accessed [today's date]).

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