Is CC2D2A p.Pro1589Arg (c.4766C>G) pathogenic?

CC2D2A p.Pro1589Arg (c.4766C>G) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely benign (0.1869); Ultra-rare (popmax 0.011%, nfe); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Pro1589Arg (c.4766C>G)?

CC2D2A p.Pro1589Arg (c.4766C>G) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Pro1589Arg (c.4766C>G) in the general population?

CC2D2A p.Pro1589Arg (c.4766C>G) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Pro1589Arg (c.4766C>G)?

AlphaMissense predicts likely benign (score 0.1869) — an in-silico prediction, not a clinical call.

CC2D2A p.Pro1589Arg

c.4766C>G · rs374301736 · VCV1520502

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.1869	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.69 · regional, not allelic
Overall
CADD	24.8	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 0.011% European (non-Finnish) · 129/1,177,888 alleles

Filtering AF 0.00937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00881%

Overall 0.00814% 131/1,610,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,131
Remaining individualsnot grpmax-eligible	0.00321%	31,162

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.Pro1589Arg
Coding: c.4766C>G
MANE Select: NM_001378615
dbSNP: rs374301736
Type: single nucleotide variant
Location: chr4:15601328 (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.Pro1589= Likely benign ★ 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-pro1589arg (accessed [today's date]).

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