Is C3 p.Arg304Trp (c.910C>T) pathogenic?

C3 p.Arg304Trp (c.910C>T) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely benign (0.3103); Very rare (popmax 0.00167%, amr).

How common is C3 p.Arg304Trp (c.910C>T) in the general population?

C3 p.Arg304Trp (c.910C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about C3 p.Arg304Trp (c.910C>T)?

AlphaMissense predicts likely benign (score 0.3103) — an in-silico prediction, not a clinical call.

C3 p.Arg304Trp

c.910C>T · rs759948962 · VCV2190840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3103	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -13.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.83	GERP -3.1, phastCons 0.011
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	17.4	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 · 1/59,992 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,566 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,992
South Asian	0.0011%	91,072
European (non-Finnish)	0.000424%	236,002

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.Arg304Trp
Coding: c.910C>T
MANE Select: NM_000064
dbSNP: rs759948962
Type: single nucleotide variant
Location: chr19:6713282 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 304: an α-helix

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

Similar variants

C3 p.Arg304Gln Uncertain significance ★★ ⚠ same residue
C3 p.Arg304= Benign/Likely benign ★★ same residue
C3 p.Arg304Pro Uncertain significance ★ ⚠ 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

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-arg304trp (accessed [today's date]).

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