Is CC2D2A p.Ser117Arg (c.351T>G) pathogenic?

CC2D2A p.Ser117Arg (c.351T>G) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.4409); Rare (popmax 0.213%, nfe); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Ser117Arg (c.351T>G)?

CC2D2A p.Ser117Arg (c.351T>G) is associated with Meckel syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Ser117Arg (c.351T>G) in the general population?

CC2D2A p.Ser117Arg (c.351T>G) is rare (popmax 0.213%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Ser117Arg (c.351T>G)?

AlphaMissense predicts ambiguous (score 0.4409) — an in-silico prediction, not a clinical call.

CC2D2A p.Ser117Arg

c.351T>G · rs186264635 · VCV198451

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4409 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.213%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.4409	ambiguous
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.4
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	18.38	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 0.213% European (non-Finnish) · 2,515/1,178,368 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.179% 2,884/1,610,380 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.213%	469
Remaining individualsnot grpmax-eligible	0.162%	618
Admixed American	0.154%	648
South Asian	0.126%	796
Finnishnot grpmax-eligible	0.0564%	1,774
Middle Eastern	0.033%	3,029
African / African-American	0.032%	3,124
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,464

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.Ser117Arg
Coding: c.351T>G
MANE Select: NM_001378615
dbSNP: rs186264635
Type: single nucleotide variant
Location: chr4:15502836 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 117: a UniProt-annotated variant site (in jbts9; uncertain significance); the 'disordered' region

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: Meckel syndrome, type 6 Joubert syndrome 9 Joubert syndrome

Similar variants

CC2D2A p.Ser117= 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-ser117arg (accessed [today's date]).

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