Is CC2D2A p.Arg423Gln (c.1268G>A) pathogenic?

CC2D2A p.Arg423Gln (c.1268G>A) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.3061); Ultra-rare (popmax 0.0713%, eas); Associated with Meckel syndrome, type 6.

What condition is associated with CC2D2A p.Arg423Gln (c.1268G>A)?

CC2D2A p.Arg423Gln (c.1268G>A) is associated with Meckel syndrome, type 6, Joubert syndrome 9, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg423Gln (c.1268G>A) in the general population?

CC2D2A p.Arg423Gln (c.1268G>A) is ultra-rare (popmax 0.0713%, eas) (gnomAD).

What do computational predictors say about CC2D2A p.Arg423Gln (c.1268G>A)?

AlphaMissense predicts likely benign (score 0.3061) — an in-silico prediction, not a clinical call.

CC2D2A p.Arg423Gln

c.1268G>A · rs780924556 · VCV1058499

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meckel syndrome, type 6

Computational evidence

Protein change
AlphaMissense	0.3061	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -6.92	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	29.7	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 0.0713% East Asian · 32/44,876 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0452%

Overall 0.0039% 63/1,613,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,402
Middle Eastern	0.033%	3,031
African / African-American	0.004%	25,009
Admixed American	0.00334%	29,970
European (non-Finnish)	0.00186%	53,620
Remaining individualsnot grpmax-eligible	0.0016%	62,474
South Asian	0.0011%	90,876

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.Arg423Gln
Coding: c.1268G>A
MANE Select: NM_001378615
dbSNP: rs780924556
Type: single nucleotide variant
Location: chr4:15527565 (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, type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 9 Joubert syndrome Meckel syndrome retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Arg423Ter Pathogenic/Likely pathogenic ★★ same residue
CC2D2A p.Arg423= 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
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-arg423gln (accessed [today's date]).

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