Is CC2D2A p.Leu474= (c.1422C>T) pathogenic?

CC2D2A p.Leu474= (c.1422C>T) is classified Likely benign in CC2D2A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00935%, afr); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Leu474= (c.1422C>T)?

CC2D2A p.Leu474= (c.1422C>T) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Leu474= (c.1422C>T) in the general population?

CC2D2A p.Leu474= (c.1422C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

CC2D2A p.Leu474=

c.1422C>T · rs377448964 · VCV1091405

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -4.1
Overall
CADD	1.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,900 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000806% 13/1,613,270 alleles · very rare exomes 8/1,461,090 · genomes 5/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,700
East Asian	0.00223%	44,886
Admixed American	0.00167%	59,880
Remaining individualsnot grpmax-eligible	0.0016%	62,450
European (non-Finnish)	0.000254%	393,212

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.Leu474=
Coding: c.1422C>T
MANE Select: NM_001378615
dbSNP: rs377448964
Type: single nucleotide variant
Location: chr4:15528682 (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.Leu474Pro Uncertain significance ★★ ⚠ 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
CC2D2A c.2004-17A>G Pathogenic/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-leu474 (accessed [today's date]).

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