Is CC2D2A p.Arg173Ter (c.517C>T) pathogenic?

CC2D2A p.Arg173Ter (c.517C>T) is classified Pathogenic in CC2D2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-08-03). Ultra-rare (popmax 0.033%, mid); Associated with CC2D2A-related disorder.

What condition is associated with CC2D2A p.Arg173Ter (c.517C>T)?

CC2D2A p.Arg173Ter (c.517C>T) is associated with CC2D2A-related disorder, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Arg173Ter (c.517C>T) in the general population?

CC2D2A p.Arg173Ter (c.517C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

CC2D2A p.Arg173Ter

c.517C>T · rs386833763 · VCV56315

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

CC2D2A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 37
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP 1.7, phastCons 0.001
Overall
CADD	33.0	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.0018% 29/1,610,958 alleles · ultra-rare exomes 27/1,458,684 · genomes 2/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
Admixed American	0.00507%	19,733
Remaining individualsnot grpmax-eligible	0.00481%	20,799
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.00153%	65,504
African / African-American	0.00134%	74,856
South Asian	0.00111%	90,066

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.Arg173Ter
Coding: c.517C>T
MANE Select: NM_001378615
dbSNP: rs386833763
Type: single nucleotide variant
Location: chr4:15510217 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 173: the 'disordered' region

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome Meckel syndrome retinitis pigmentosa 93 COACH syndrome 2

Similar variants

CC2D2A p.Arg173Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A p.Arg173= 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-arg173ter (accessed [today's date]).

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