Is CC2D2A p.Glu282Ala (c.845A>C) pathogenic?

CC2D2A p.Glu282Ala (c.845A>C) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.3084); Very rare (popmax 0.00801%, afr); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Glu282Ala (c.845A>C)?

CC2D2A p.Glu282Ala (c.845A>C) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Glu282Ala (c.845A>C) in the general population?

CC2D2A p.Glu282Ala (c.845A>C) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about CC2D2A p.Glu282Ala (c.845A>C)?

AlphaMissense predicts likely benign (score 0.3084) — an in-silico prediction, not a clinical call.

CC2D2A p.Glu282Ala

c.845A>C · rs760099299 · VCV1470473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.3084	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	23.8	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 0.00801% African / African-American · 6/74,944 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00266% 43/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,491
Remaining individualsnot grpmax-eligible	0.0032%	31,231
European (non-Finnish)	0.00297%	33,710

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.Glu282Ala
Coding: c.845A>C
MANE Select: NM_001378615
dbSNP: rs760099299
Type: single nucleotide variant
Location: chr4:15514834 (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 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
CC2D2A c.2486+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-glu282ala (accessed [today's date]).

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