Is C3 p.Pro1020Leu (c.3059C>T) pathogenic?

C3 p.Pro1020Leu (c.3059C>T) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-18). AlphaMissense: likely pathogenic (0.6858); Absent from gnomAD v4.1; Associated with C3-related disorder.

What condition is associated with C3 p.Pro1020Leu (c.3059C>T)?

C3 p.Pro1020Leu (c.3059C>T) is associated with C3-related disorder, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Pro1020Leu (c.3059C>T) in the general population?

C3 p.Pro1020Leu (c.3059C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C3 p.Pro1020Leu (c.3059C>T)?

AlphaMissense predicts likely pathogenic (score 0.6858) — an in-silico prediction, not a clinical call.

C3 p.Pro1020Leu

c.3059C>T · rs1918258356 · VCV2631766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

C3-related disorder

Computational evidence

Protein change
AlphaMissense	0.6858	likely pathogenic
REVEL	0.543	indeterminate
SaProt	LLR -13.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C3
Protein: p.Pro1020Leu
Coding: c.3059C>T
MANE Select: NM_000064
dbSNP: rs1918258356
Type: single nucleotide variant
Location: chr19:6694526 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1020: an α-helix; a disulfide bond

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

Disease context

C3-related disorder

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

Similar variants

C3 p.Pro1020= Likely benign ★ 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-pro1020leu (accessed [today's date]).

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