Is CC2D2A p.Ile175fs (c.523del) pathogenic?

CC2D2A p.Ile175fs (c.523del) is classified Pathogenic in CC2D2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). Very rare (popmax 0.00017%, nfe); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Ile175fs (c.523del)?

CC2D2A p.Ile175fs (c.523del) is associated with Joubert syndrome, Joubert syndrome 9, Meckel syndrome (ClinVar).

How common is CC2D2A p.Ile175fs (c.523del) in the general population?

CC2D2A p.Ile175fs (c.523del) is very rare (popmax 0.00017%, nfe) (gnomAD).

CC2D2A p.Ile175fs

c.523del · rs1338343514 · VCV2950561

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 37
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.43	GERP -4.5, phastCons 0.02
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,010 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,498 alleles · very rare

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.Ile175fs
Coding: c.523del
MANE Select: NM_001378615
dbSNP: rs1338343514
Type: Deletion
Location: chr4:15510219 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 175: 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: Joubert syndrome 9 Meckel syndrome

Similar variants

CC2D2A c.3289delG Pathogenic ★★ same condition
CC2D2A c.3597_3600del Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.4179+1del Pathogenic ★★ same condition
CC2D2A p.Ala1197fs Pathogenic/Likely pathogenic ★★ same condition
CC2D2A p.Ala447fs Pathogenic/Likely pathogenic ★★ same condition
CC2D2A p.Asp1227fs Likely pathogenic ★★ same condition
CC2D2A p.Asp1489fs Pathogenic/Likely pathogenic ★★ same condition
CC2D2A p.Gln280fs 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-ile175fs (accessed [today's date]).

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