Is C2CD3 p.Pro569Arg (c.1706C>G) pathogenic?

C2CD3 p.Pro569Arg (c.1706C>G) is classified Conflicting classifications of pathogenicity in C2CD3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-23). AlphaMissense: likely benign (0.0903); Ultra-rare (popmax 0.0214%, afr); Associated with Inborn genetic diseases.

What condition is associated with C2CD3 p.Pro569Arg (c.1706C>G)?

C2CD3 p.Pro569Arg (c.1706C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C2CD3 p.Pro569Arg (c.1706C>G) in the general population?

C2CD3 p.Pro569Arg (c.1706C>G) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about C2CD3 p.Pro569Arg (c.1706C>G)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

C2CD3 p.Pro569Arg

c.1706C>G · rs370227049 · VCV2416087

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor loss, 4 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.9	GERP 0.087, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	19.59	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 0.0214% African / African-American · 16/74,904 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00124% 20/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,681
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Admixed American	0.00167%	59,962

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.Pro569Arg
Coding: c.1706C>G
MANE Select: NM_001286577
dbSNP: rs370227049
Type: single nucleotide variant
Location: chr11:74114408 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 569: the c2 1 domain

Full C2CD3 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

C2CD3 c.2085+5G>A Uncertain significance ★★ same condition
C2CD3 c.4951+6C>T Uncertain significance ★★ same condition
C2CD3 p.Ala1382Pro Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala1777Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Ala95Thr Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1122Ile Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1145His Uncertain significance ★★ ⚠ same condition
C2CD3 p.Arg1183His 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/c2cd3-p-pro569arg (accessed [today's date]).

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