Is CC2D2A p.Ser422fs (c.1263_1264insGGCATGTTTTGGC) pathogenic?

CC2D2A p.Ser422fs (c.12631264insGGCATGTTTTGGC) is classified Pathogenic in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). Very rare (popmax 0.000509%, nfe); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Ser422fs (c.1263_1264insGGCATGTTTTGGC)?

CC2D2A p.Ser422fs (c.1263_1264insGGCATGTTTTGGC) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Ser422fs (c.1263_1264insGGCATGTTTTGGC) in the general population?

CC2D2A p.Ser422fs (c.1263_1264insGGCATGTTTTGGC) is very rare (popmax 0.000509%, nfe) (gnomAD).

CC2D2A p.Ser422fs

c.1263_1264insGGCATGTTTTGGC · rs762998472 · VCV2949355

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000509%, 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 12 of 37
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.2	GERP -5.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,714 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,588 alleles · very rare exomes 6/1,461,252 · genomes 0/152,336 · joint denominator

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.Ser422fs
Coding: c.1263_1264insGGCATGTTTTGGC
MANE Select: NM_001378615
dbSNP: rs762998472
Type: Insertion
Location: chr4:15527560 (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

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

Also linked: Meckel syndrome

Similar variants

CC2D2A p.Ser422Arg Uncertain significance ★ ⚠ same residue
CC2D2A p.Gln156_Glu157insAlaGlyArgGlyGlySerArgLeuTer Pathogenic ★ same condition
CC2D2A c.2625+12_2625+13insTCA Likely benign ★ same condition
CC2D2A c.4066-13_4066-12insG Likely benign ★ same condition
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

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-ser422fs (accessed [today's date]).

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