Is CC2D2A p.Arg423Ter (c.1267C>T) pathogenic?

CC2D2A p.Arg423Ter (c.1267C>T) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00446%, eas); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Arg423Ter (c.1267C>T)?

CC2D2A p.Arg423Ter (c.1267C>T) is associated with Meckel syndrome, Joubert syndrome 1, Meckel syndrome, type 6 (ClinVar).

How common is CC2D2A p.Arg423Ter (c.1267C>T) in the general population?

CC2D2A p.Arg423Ter (c.1267C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

CC2D2A p.Arg423Ter

c.1267C>T · rs757208121 · VCV411851

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 0.00446%, eas)

Conditions

Meckel syndrome

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 12 of 37
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 1
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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00062% 10/1,613,208 alleles · very rare exomes 8/1,461,120 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
Admixed American	0.00167%	59,930
African / African-American	0.00134%	74,878
European (non-Finnish)	0.000509%	196,603

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.Arg423Ter
Coding: c.1267C>T
MANE Select: NM_001378615
dbSNP: rs757208121
Type: single nucleotide variant
Location: chr4:15527564 (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

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

Also linked: Joubert syndrome 1 Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Arg423Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A p.Arg423= Likely benign ★ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1149+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

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-arg423ter (accessed [today's date]).

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