Is CC2D2A p.Glu998= (c.2994A>G) pathogenic?

CC2D2A p.Glu998= (c.2994A>G) is classified Likely benign in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). Ultra-rare (popmax 0.018%, mid); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Glu998= (c.2994A>G)?

CC2D2A p.Glu998= (c.2994A>G) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Glu998= (c.2994A>G) in the general population?

CC2D2A p.Glu998= (c.2994A>G) is ultra-rare (popmax 0.018%, mid) (gnomAD).

CC2D2A p.Glu998=

c.2994A>G · rs1044670589 · VCV703682

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, mid)

Conditions

Joubert syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.9	GERP 1.2, phastCons 1
Overall
CADD	9.068	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% Middle Eastern · 1/5,550 alleles

Filtering AF 0.000275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000177%

Overall 0.000616% 9/1,461,614 alleles · ultra-rare exomes 7/1,309,386 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.018%	5,550
Remaining individualsnot grpmax-eligible	0.00175%	57,074
European (non-Finnish)	0.00066%	151,497

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.Glu998=
Coding: c.2994A>G
MANE Select: NM_001378615
dbSNP: rs1044670589
Type: single nucleotide variant
Location: chr4:15560602 (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.Glu998Val Likely pathogenic ★ ⚠ 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-glu998 (accessed [today's date]).

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