Is C3 p.Arg425His (c.1274G>A) pathogenic?

C3 p.Arg425His (c.1274G>A) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-16). AlphaMissense: likely benign (0.0843); Very rare (popmax 0.00446%, eas).

How common is C3 p.Arg425His (c.1274G>A) in the general population?

C3 p.Arg425His (c.1274G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about C3 p.Arg425His (c.1274G>A)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

C3 p.Arg425His

c.1274G>A · rs201714568 · VCV1443552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -7.95	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 -1.8	GERP -1.8
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	18.68	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 · 2/44,868 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00103% 15/1,459,876 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,434
South Asian	0.0022%	45,536
European (non-Finnish)	0.000932%	107,259

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.Arg425His
Coding: c.1274G>A
MANE Select: NM_000064
dbSNP: rs201714568
Type: single nucleotide variant
Location: chr19:6711192 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 425: a β-strand

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

Similar variants

C3 p.Arg425Leu Uncertain significance ★★ ⚠ same residue
C3 p.Arg425Cys 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

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-arg425his (accessed [today's date]).

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