Is CC2D2A p.Arg489Ter (c.1465C>T) pathogenic?

CC2D2A p.Arg489Ter (c.1465C>T) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-08). Very rare (popmax 0.00675%, eas); Associated with Abnormality of prenatal development or birth.

What condition is associated with CC2D2A p.Arg489Ter (c.1465C>T)?

CC2D2A p.Arg489Ter (c.1465C>T) is associated with Abnormality of prenatal development or birth, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Arg489Ter (c.1465C>T) in the general population?

CC2D2A p.Arg489Ter (c.1465C>T) is very rare (popmax 0.00675%, eas) (gnomAD).

CC2D2A p.Arg489Ter

c.1465C>T · rs145678228 · VCV1180720

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00675%, eas)

Conditions

Abnormality of prenatal development or birth

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 13 of 37
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.063	GERP -0.55, phastCons 0.12
Overall
CADD	35.0	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 0.00675% East Asian · 3/44,434 alleles

Filtering AF 0.00179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00091%

Overall 0.000815% 13/1,594,878 alleles · very rare exomes 11/1,442,614 · genomes 2/152,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00675%	14,811
South Asian	0.00451%	22,153
Admixed American	0.00171%	58,426
Remaining individualsnot grpmax-eligible	0.00162%	61,742
European (non-Finnish)	0.000343%	291,848

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.Arg489Ter
Coding: c.1465C>T
MANE Select: NM_001378615
dbSNP: rs145678228
Type: single nucleotide variant
Location: chr4:15528725 (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

Abnormality of prenatal development or birth — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Arg489= Uncertain significance ★ same residue
CC2D2A p.Arg489Gln 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>C Likely pathogenic ★★ same condition
CC2D2A c.1466+1G>A Likely pathogenic ★★ same condition
CC2D2A c.1466+2T>C Likely pathogenic ★★ same condition
CC2D2A c.1608-2A>G 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-arg489ter (accessed [today's date]).

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