Is CC2D2A p.Ala216Pro (c.646G>C) pathogenic?

CC2D2A p.Ala216Pro (c.646G>C) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0833); Very rare (popmax 0.00552%, afr); Associated with Joubert syndrome 9.

What condition is associated with CC2D2A p.Ala216Pro (c.646G>C)?

CC2D2A p.Ala216Pro (c.646G>C) is associated with Joubert syndrome 9, Meckel syndrome, type 6, Joubert syndrome (ClinVar).

How common is CC2D2A p.Ala216Pro (c.646G>C) in the general population?

CC2D2A p.Ala216Pro (c.646G>C) is very rare (popmax 0.00552%, afr) (gnomAD).

What do computational predictors say about CC2D2A p.Ala216Pro (c.646G>C)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

CC2D2A p.Ala216Pro

c.646G>C · rs539372200 · VCV2146535

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00552%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 9

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.00	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 2.2	GERP -0.29, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	13.21	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 0.00552% African / African-American · 4/72,456 alleles

Filtering AF 0.00179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.000443% 7/1,579,230 alleles · very rare exomes 3/1,426,974 · genomes 4/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00552%	18,114
Remaining individualsnot grpmax-eligible	0.00491%	20,359

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.Ala216Pro
Coding: c.646G>C
MANE Select: NM_001378615
dbSNP: rs539372200
Type: single nucleotide variant
Location: chr4:15511352 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 216: the 'disordered' region

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome Meckel syndrome retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Ala216Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A p.Ala216= Likely benign ★ same residue
CC2D2A p.Ala216Gly Uncertain significance ★ ⚠ same residue
CC2D2A p.Ala216Glu Likely benign ★ same residue
CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.1149+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.123+2T>G Likely pathogenic ★★ same condition
CC2D2A c.1359+1G>A 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-ala216pro (accessed [today's date]).

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