Is CC2D2A p.Ser1580fs (c.4737_4738dup) pathogenic?

CC2D2A p.Ser1580fs (c.47374738dup) is classified Pathogenic in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-13). Very rare (popmax 0.0011%, sas); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Ser1580fs (c.4737_4738dup)?

CC2D2A p.Ser1580fs (c.4737_4738dup) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Ser1580fs (c.4737_4738dup) in the general population?

CC2D2A p.Ser1580fs (c.4737_4738dup) is very rare (popmax 0.0011%, sas) (gnomAD).

CC2D2A p.Ser1580fs

c.4737_4738dup · VCV4784067

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Meckel syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (37 of 37) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.74	GERP -4.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,912 alleles

Overall 6.85e-05% 1/1,460,440 alleles · very rare

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.Ser1580fs
Coding: c.4737_4738dup
MANE Select: NM_001378615
Type: Microsatellite
Location: chr4:15601296 (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 p.Ser1580Gly Uncertain significance ★★ ⚠ same residue
CC2D2A p.Ser1580= Likely benign ★ same residue
CC2D2A c.3975+4_3975+7del Pathogenic ★★ same condition
CC2D2A p.Glu224del Uncertain significance ★★ same condition
CC2D2A p.Lys594del Uncertain significance ★★ same condition
CC2D2A c.3014+24_3014+26del Likely benign ★★ same condition
CC2D2A p.Glu229del Benign/Likely benign ★★ same condition
CC2D2A p.Glu140delinsGlyGlyArgSerGlnAspGlyArgIleGlyThrAlaProValTyrSerSerGlnArgGluArgArgArgArgArgTer 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-ser1580fs (accessed [today's date]).

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