Is C3 p.Gln652Pro (c.1955A>C) pathogenic?

C3 p.Gln652Pro (c.1955A>C) is classified Uncertain significance in C3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.2162); Ultra-rare (popmax 0.0735%, eas); Associated with Inborn genetic diseases.

What condition is associated with C3 p.Gln652Pro (c.1955A>C)?

C3 p.Gln652Pro (c.1955A>C) is associated with Inborn genetic diseases (ClinVar).

How common is C3 p.Gln652Pro (c.1955A>C) in the general population?

C3 p.Gln652Pro (c.1955A>C) is ultra-rare (popmax 0.0735%, eas) (gnomAD).

What do computational predictors say about C3 p.Gln652Pro (c.1955A>C)?

AlphaMissense predicts likely benign (score 0.2162) — an in-silico prediction, not a clinical call.

C3 p.Gln652Pro

c.1955A>C · rs748054406 · VCV2200865

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0735%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2162	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -7.41	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 2.5	GERP -3.1, phastCons 0.28
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	17.15	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 0.0735% East Asian · 33/44,870 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0471%

Overall 0.00217% 35/1,613,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0735%	1,360
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asian	0.0011%	91,074

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.Gln652Pro
Coding: c.1955A>C
MANE Select: NM_000064
dbSNP: rs748054406
Type: single nucleotide variant
Location: chr19:6707820 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 652: 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.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
C3 p.Arg1441Met 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-gln652pro (accessed [today's date]).

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