Is C3 p.Pro1223Ser (c.3667C>T) pathogenic?

C3 p.Pro1223Ser (c.3667C>T) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-03). AlphaMissense: likely benign (0.0877); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with C3 p.Pro1223Ser (c.3667C>T)?

C3 p.Pro1223Ser (c.3667C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C3 p.Pro1223Ser (c.3667C>T) in the general population?

C3 p.Pro1223Ser (c.3667C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about C3 p.Pro1223Ser (c.3667C>T)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

C3 p.Pro1223Ser

c.3667C>T · rs771497419 · VCV1910079

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.60	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 3	GERP -0.42, phastCons 0.28
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	17.18	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 0.0167% Middle Eastern · 1/5,992 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000889% 13/1,461,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,992
European (non-Finnish)	0.00102%	98,336

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.Pro1223Ser
Coding: c.3667C>T
MANE Select: NM_000064
dbSNP: rs771497419
Type: single nucleotide variant
Location: chr19:6686267 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1223: a β-strand; a disulfide bond

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.Pro1223Ala Uncertain significance ★ ⚠ same residue
C3 p.Pro1223Leu 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

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-pro1223ser (accessed [today's date]).

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