Is CC2D2A p.Ala1329Pro (c.3985G>C) pathogenic?

CC2D2A p.Ala1329Pro (c.3985G>C) is classified Uncertain significance in CC2D2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-05). AlphaMissense: likely pathogenic (0.9523); Ultra-rare (popmax 0.012%, afr); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Ala1329Pro (c.3985G>C)?

CC2D2A p.Ala1329Pro (c.3985G>C) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Ala1329Pro (c.3985G>C) in the general population?

CC2D2A p.Ala1329Pro (c.3985G>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CC2D2A p.Ala1329Pro (c.3985G>C)?

AlphaMissense predicts likely pathogenic (score 0.9523) — an in-silico prediction, not a clinical call.

CC2D2A p.Ala1329Pro

c.3985G>C · rs951039594 · VCV422171

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.9523	likely pathogenic · top 4% in CC2D2A
REVEL	0.645	pathogenic-leaning
SaProt	LLR -15.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 6,108 bp · p 8.6e-05 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.012% African / African-American · 9/74,810 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000559% 9/1,609,402 alleles · ultra-rare exomes 0/1,457,250 · genomes 9/152,152 · joint denominator

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.Ala1329Pro
Coding: c.3985G>C
MANE Select: NM_001378615
dbSNP: rs951039594
Type: single nucleotide variant
Location: chr4:15586166 (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-ala1329pro (accessed [today's date]).

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