Is CC2D2A p.Arg1218Ter (c.3652C>T) pathogenic?

CC2D2A p.Arg1218Ter (c.3652C>T) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-09). Very rare (popmax 0.00392%, amr); Associated with CC2D2A-related disorder.

What condition is associated with CC2D2A p.Arg1218Ter (c.3652C>T)?

CC2D2A p.Arg1218Ter (c.3652C>T) is associated with CC2D2A-related disorder, Meckel syndrome, type 6, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg1218Ter (c.3652C>T) in the general population?

CC2D2A p.Arg1218Ter (c.3652C>T) is very rare (popmax 0.00392%, amr) (gnomAD).

CC2D2A p.Arg1218Ter

c.3652C>T · rs375278294 · VCV238273

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00392%, amr)

Conditions

CC2D2A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 29 of 37
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.6, phastCons 0.99
Overall
CADD	36.0	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 0.00392% Admixed American · 2/50,976 alleles

Filtering AF 0.000651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000786% 11/1,398,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00392%	25,488
European (non-Finnish)	0.000785%	127,412

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.Arg1218Ter
Coding: c.3652C>T
MANE Select: NM_001378615
dbSNP: rs375278294
Type: single nucleotide variant
Location: chr4:15574207 (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: Meckel syndrome, type 6 Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Arg1218= Conflicting classifications of pathogenicity ★ same residue
CC2D2A p.Arg1218Gln Conflicting classifications of pathogenicity ★ ⚠ 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>A Pathogenic/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

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-arg1218ter (accessed [today's date]).

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