Is CC2D2A p.Pro1250fs (c.3744_3747dup) pathogenic?

CC2D2A p.Pro1250fs (c.37443747dup) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). Very rare (popmax 0.00137%, afr); Associated with CC2D2A-related disorder.

What condition is associated with CC2D2A p.Pro1250fs (c.3744_3747dup)?

CC2D2A p.Pro1250fs (c.3744_3747dup) is associated with CC2D2A-related disorder, Joubert syndrome 9, Joubert syndrome (ClinVar).

How common is CC2D2A p.Pro1250fs (c.3744_3747dup) in the general population?

CC2D2A p.Pro1250fs (c.3744_3747dup) is very rare (popmax 0.00137%, afr) (gnomAD).

CC2D2A p.Pro1250fs

c.3744_3747dup · rs863225171 · VCV217599

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Conditions

CC2D2A-related disorder

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 29 of 37
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP 0.39, 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 0.00137% African / African-American · 1/73,046 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000322%

Overall 0.000709% 11/1,551,270 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	73,046
European (non-Finnish)	0.000872%	114,677

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.Pro1250fs
Coding: c.3744_3747dup
MANE Select: NM_001378615
dbSNP: rs863225171
Type: Duplication
Location: chr4:15574297 (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

Also linked: Joubert syndrome 9 Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Ala1362fs Pathogenic/Likely pathogenic ★★ same condition
CC2D2A p.Glu1259Ter Pathogenic ★★ same condition
CC2D2A p.Phe744fs Pathogenic/Likely pathogenic ★★ same condition
CC2D2A p.Val1583fs Uncertain significance ★★ same condition
CC2D2A c.1150-15dup Likely benign ★★ same condition
CC2D2A c.2922+10dup Benign/Likely benign ★★ same condition
CC2D2A p.Ala1491fs Pathogenic ★ same condition
CC2D2A p.Arg103fs 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-pro1250fs (accessed [today's date]).

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