Is CC2D2A p.Pro81= (c.243A>G) pathogenic?

CC2D2A p.Pro81= (c.243A>G) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-08). Very rare (popmax 0.00568%, nfe); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Pro81= (c.243A>G)?

CC2D2A p.Pro81= (c.243A>G) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Pro81= (c.243A>G) in the general population?

CC2D2A p.Pro81= (c.243A>G) is very rare (popmax 0.00568%, nfe) (gnomAD).

CC2D2A p.Pro81=

c.243A>G · rs766042434 · VCV596026

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.115	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.6	GERP -4.5
Overall
CADD	0.661	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00568% European (non-Finnish) · 67/1,178,706 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00428% 69/1,611,754 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,593
Admixed American	0.00167%	59,810
African / African-American	0.00134%	74,828

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: CC2D2A
Protein: p.Pro81=
Coding: c.243A>G
MANE Select: NM_001378615
dbSNP: rs766042434
Type: single nucleotide variant
Location: chr4:15480823 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 81: the 'disordered' region

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome

Similar variants

CC2D2A p.Pro81Ala Uncertain significance ★ ⚠ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.123+2T>G Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>C Likely pathogenic ★★ same condition
CC2D2A c.1466+1G>A Likely pathogenic ★★ same condition
CC2D2A c.1466+2T>C Likely pathogenic ★★ same condition
CC2D2A c.1608-2A>G Likely pathogenic ★★ same condition
CC2D2A c.2004-17A>G Pathogenic/Likely pathogenic ★★ 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/cc2d2a-p-pro81 (accessed [today's date]).

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