Is CC2D2A p.Lys40Arg (c.119A>G) pathogenic?

CC2D2A p.Lys40Arg (c.119A>G) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-13). AlphaMissense: likely benign (0.0739); Very rare (popmax 0.00196%, amr); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Lys40Arg (c.119A>G)?

CC2D2A p.Lys40Arg (c.119A>G) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Lys40Arg (c.119A>G) in the general population?

CC2D2A p.Lys40Arg (c.119A>G) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about CC2D2A p.Lys40Arg (c.119A>G)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

CC2D2A p.Lys40Arg

c.119A>G · rs780010340 · VCV2085756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -0.41, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	17.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/51,108 alleles

Overall 0.000129% 2/1,552,358 alleles · very rare exomes 2/1,399,998 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	51,108
European (non-Finnish)	8.72e-05%	1,147,018

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.Lys40Arg
Coding: c.119A>G
MANE Select: NM_001378615
dbSNP: rs780010340
Type: single nucleotide variant
Location: chr4:15478802 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 40: the 'disordered' region

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.Lys40Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A p.Lys40Gln 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

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-lys40arg (accessed [today's date]).

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