Is CC2D2A p.Ile1508fs (c.4522del) pathogenic?

CC2D2A p.Ile1508fs (c.4522del) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-15). Very rare (popmax 0.00455%, eas); Associated with COACH syndrome 2.

What condition is associated with CC2D2A p.Ile1508fs (c.4522del)?

CC2D2A p.Ile1508fs (c.4522del) is associated with COACH syndrome 2, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Ile1508fs (c.4522del) in the general population?

CC2D2A p.Ile1508fs (c.4522del) is very rare (popmax 0.00455%, eas) (gnomAD).

How is Joubert syndrome with hepatic defect inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CC2D2A p.Ile1508fs

c.4522del · rs775292940 · VCV1427276

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00455%, eas)

Conditions

COACH syndrome 2

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 36 of 37
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Overall
CADD	34.0	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 0.00455% East Asian · 2/43,962 alleles

Filtering AF 0.000754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000282%

Overall 0.00032% 5/1,561,472 alleles · very rare exomes 3/1,409,528 · genomes 2/151,944 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00455%	21,981
Admixed American	0.00374%	26,757
European (non-Finnish)	8.7e-05%	1,149,787

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.Ile1508fs
Coding: c.4522del
MANE Select: NM_001378615
dbSNP: rs775292940
Type: Deletion
Location: chr4:15599549 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46

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

Disease context

COACH syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome Meckel syndrome retinitis pigmentosa 93

For Joubert syndrome with hepatic defect (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

CC2D2A p.Ile1508Leu Uncertain significance ★ ⚠ same residue
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

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-ile1508fs (accessed [today's date]).

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