Is C3 p.Pro1074Arg (c.3221C>G) pathogenic?

C3 p.Pro1074Arg (c.3221C>G) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.7352); Very rare (popmax 0.00111%, sas); Associated with Inborn genetic diseases.

What condition is associated with C3 p.Pro1074Arg (c.3221C>G)?

C3 p.Pro1074Arg (c.3221C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C3 p.Pro1074Arg (c.3221C>G) in the general population?

C3 p.Pro1074Arg (c.3221C>G) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about C3 p.Pro1074Arg (c.3221C>G)?

AlphaMissense predicts likely pathogenic (score 0.7352) — an in-silico prediction, not a clinical call.

C3 p.Pro1074Arg

c.3221C>G · VCV4217348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7352	likely pathogenic
REVEL	0.213	benign-leaning
SaProt	LLR -14.05	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.6	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 0.00111% South Asian · 1/90,402 alleles

Overall 6.21e-05% 1/1,610,684 alleles · very rare exomes 1/1,458,472 · genomes 0/152,212 · joint denominator

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.Pro1074Arg
Coding: c.3221C>G
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6693421 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1074: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C3 p.Pro1074Ser Uncertain significance ★ ⚠ same residue
C3 p.Ala1214Pro Uncertain significance ★★ ⚠ same condition
C3 p.Ala642Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala655Thr Uncertain significance ★★ ⚠ same condition
C3 p.Ala719Val Uncertain significance ★★ ⚠ same condition
C3 p.Arg1254His Uncertain significance ★★ ⚠ same condition
C3 p.Arg1393Gln Uncertain significance ★★ ⚠ same condition
C3 p.Arg1427Thr 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-pro1074arg (accessed [today's date]).

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