Is CC2D2A p.Arg1618Ser (c.4852C>A) pathogenic?

CC2D2A p.Arg1618Ser (c.4852C>A) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-05). AlphaMissense: likely pathogenic (0.7343); Very rare (popmax 9e-05%, nfe); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Arg1618Ser (c.4852C>A)?

CC2D2A p.Arg1618Ser (c.4852C>A) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg1618Ser (c.4852C>A) in the general population?

CC2D2A p.Arg1618Ser (c.4852C>A) is very rare (popmax 9e-05%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Arg1618Ser (c.4852C>A)?

AlphaMissense predicts likely pathogenic (score 0.7343) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg1618Ser

c.4852C>A · rs201219078 · VCV955483

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.7343	likely pathogenic
REVEL	0.515	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.69 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9e-05% European (non-Finnish) · 1/1,111,706 alleles

Overall 6.75e-05% 1/1,482,572 alleles · very rare exomes 1/1,330,304 · genomes 0/152,268 · joint denominator

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.Arg1618Ser
Coding: c.4852C>A
MANE Select: NM_001378615
dbSNP: rs201219078
Type: single nucleotide variant
Location: chr4:15601414 (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

Similar variants

CC2D2A p.Arg1618Cys Uncertain significance ★★ ⚠ same residue
CC2D2A p.Arg1618Gly Uncertain significance ★ same residue
CC2D2A p.Arg1618= Likely benign ★ same residue
CC2D2A p.Arg1618His 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

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-arg1618ser (accessed [today's date]).

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