Is CC2D2A p.Arg130Cys (c.388C>T) pathogenic?

CC2D2A p.Arg130Cys (c.388C>T) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-16). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with CC2D2A p.Arg130Cys (c.388C>T)?

CC2D2A p.Arg130Cys (c.388C>T) is associated with Inborn genetic diseases, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Arg130Cys (c.388C>T) in the general population?

CC2D2A p.Arg130Cys (c.388C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about CC2D2A p.Arg130Cys (c.388C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg130Cys

c.388C>T · rs886042463 · VCV282716

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	25.5	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 0.0134% East Asian · 6/44,846 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00397% 64/1,611,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,474
African / African-American	0.00934%	10,709
Remaining individualsnot grpmax-eligible	0.00481%	20,811
South Asian	0.00443%	22,587
European (non-Finnish)	0.00365%	27,422
Admixed American	0.00167%	59,770

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.Arg130Cys
Coding: c.388C>T
MANE Select: NM_001378615
dbSNP: rs886042463
Type: single nucleotide variant
Location: chr4:15502873 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 130: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Arg130His Uncertain significance ★★ ⚠ same residue
CC2D2A p.Arg130= Likely benign ★ same residue
CC2D2A p.Arg130Leu 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

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-arg130cys (accessed [today's date]).

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