Is C3 p.Ala1065Pro (c.3193G>C) pathogenic?

C3 p.Ala1065Pro (c.3193G>C) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). AlphaMissense: likely pathogenic (0.9433); Absent from gnomAD v4.1.

How common is C3 p.Ala1065Pro (c.3193G>C) in the general population?

C3 p.Ala1065Pro (c.3193G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C3 p.Ala1065Pro (c.3193G>C)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

C3 p.Ala1065Pro

c.3193G>C · rs2512242945 · VCV2823341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic · top 9% in C3
REVEL	0.29	benign-leaning
SaProt	LLR -12.84	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	25.9	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

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.Ala1065Pro
Coding: c.3193G>C
MANE Select: NM_000064
dbSNP: rs2512242945
Type: single nucleotide variant
Location: chr19:6693449 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1065: a disulfide bond

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

Similar variants

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
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ same type
C3 p.Ile1157Thr 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-ala1065pro (accessed [today's date]).

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