Is CC2D2A p.Arg520Ter (c.1558C>T) pathogenic?

CC2D2A p.Arg520Ter (c.1558C>T) is classified Pathogenic/Likely pathogenic in CC2D2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). Very rare (popmax 0.00486%, nfe); Associated with Meckel syndrome, type 6.

What condition is associated with CC2D2A p.Arg520Ter (c.1558C>T)?

CC2D2A p.Arg520Ter (c.1558C>T) is associated with Meckel syndrome, type 6, Joubert syndrome 9, Joubert syndrome (ClinVar).

How common is CC2D2A p.Arg520Ter (c.1558C>T) in the general population?

CC2D2A p.Arg520Ter (c.1558C>T) is very rare (popmax 0.00486%, nfe) (gnomAD).

CC2D2A p.Arg520Ter

c.1558C>T · rs781252161 · VCV217618

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00486%, nfe)

Conditions

Meckel syndrome, type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 37
Splicing
SpliceAI	Δ0.37	donor loss · deltas
Pangolin	Δ0.29	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 0.49, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00486% European (non-Finnish) · 57/1,171,774 alleles

Filtering AF 0.0038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00347%

Overall 0.00364% 58/1,594,930 alleles · very rare exomes 57/1,442,804 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00486%	20,557
South Asian	0.00115%	86,780

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.Arg520Ter
Coding: c.1558C>T
MANE Select: NM_001378615
dbSNP: rs781252161
Type: single nucleotide variant
Location: chr4:15533284 (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 COACH syndrome 2 COACH syndrome 1

Similar variants

CC2D2A p.Arg520= 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
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-arg520ter (accessed [today's date]).

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