Is C3 p.Val619Met (c.1855G>A) pathogenic?

C3 p.Val619Met (c.1855G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0899); Ultra-rare (popmax 0.0925%, nfe); Associated with C3 glomerulonephritis.

What condition is associated with C3 p.Val619Met (c.1855G>A)?

C3 p.Val619Met (c.1855G>A) is associated with C3 glomerulonephritis, kidney disorder, age related macular degeneration 9 (ClinVar).

How common is C3 p.Val619Met (c.1855G>A) in the general population?

C3 p.Val619Met (c.1855G>A) is ultra-rare (popmax 0.0925%, nfe) (gnomAD).

What do computational predictors say about C3 p.Val619Met (c.1855G>A)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

C3 p.Val619Met

c.1855G>A · rs146613648 · VCV330316

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0925%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

C3 glomerulonephritis

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.05	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 -0.88	GERP -0.27
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	17.34	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 0.0925% European (non-Finnish) · 1,091/1,180,018 alleles

Filtering AF 0.0878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0861%

Overall 0.0728% 1,175/1,613,726 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0925%	1,082
Finnishnot grpmax-eligible	0.0502%	1,993
Remaining individualsnot grpmax-eligible	0.048%	2,083
African / African-American	0.0174%	5,761
Admixed American	0.00833%	11,998
East Asian	0.00446%	22,443
South Asian	0.0022%	45,541

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.Val619Met
Coding: c.1855G>A
MANE Select: NM_000064
dbSNP: rs146613648
Type: single nucleotide variant
Location: chr19:6707920 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 619: an α-helix; a disulfide bond

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

Disease context

C3 glomerulonephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: kidney disorder age related macular degeneration 9 atypical hemolytic-uremic syndrome with C3 anomaly complement component 3 deficiency

Similar variants

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
C3 c.683-3C>A Uncertain significance ★★ 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-val619met (accessed [today's date]).

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