Is C2CD3 p.Pro552= (c.1656A>G) pathogenic?

C2CD3 p.Pro552= (c.1656A>G) is classified Benign/Likely benign in C2CD3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 28.6%, eas) — too common for a highly-penetrant pathogenic allele.

C2CD3 p.Pro552=

Q: How common is C2CD3 p.Pro552= (c.1656A>G) in the general population?

C2CD3 p.Pro552= (c.1656A>G) is common (popmax 28.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1656A>G · rs10898957 · VCV1225887

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 28.6%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.5, phastCons 1
Overall
CADD	7.744	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.6% East Asian · 12,827/44,844 alleles

Filtering AF 28.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 28%

Overall 18.4% 296,337/1,613,272 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	32.4%	3
East Asiangrpmax	28.6%	3
South Asian	22.8%	4
Remaining individualsnot grpmax-eligible	18%	6
European (non-Finnish)	17.8%	6
Ashkenazi Jewishnot grpmax-eligible	17.7%	6
Amishnot grpmax-eligible	12.4%	8
African / African-American	11.4%	9
Admixed American	10.8%	9
Middle Eastern	10.3%	10

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: C2CD3
Protein: p.Pro552=
Coding: c.1656A>G
MANE Select: NM_001286577
dbSNP: rs10898957
Type: single nucleotide variant
Location: chr11:74114458 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 552: the c2 1 domain; the 'disordered' region

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 p.Pro552Gln Uncertain significance ★ ⚠ same residue
C2CD3 p.Pro552Leu Uncertain significance ★ same residue
C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ 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/c2cd3-p-pro552 (accessed [today's date]).

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