Is CC2D2A p.Pro721Ser (c.2161C>T) pathogenic?

CC2D2A p.Pro721Ser (c.2161C>T) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9533); Low-frequency (popmax 1.01%, sas); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Pro721Ser (c.2161C>T)?

CC2D2A p.Pro721Ser (c.2161C>T) is associated with Meckel syndrome, Joubert syndrome 1, Meckel syndrome, type 6 (ClinVar).

How common is CC2D2A p.Pro721Ser (c.2161C>T) in the general population?

CC2D2A p.Pro721Ser (c.2161C>T) is low-frequency (popmax 1.01%, sas) (gnomAD).

What do computational predictors say about CC2D2A p.Pro721Ser (c.2161C>T)?

AlphaMissense predicts likely pathogenic (score 0.9533) — an in-silico prediction, not a clinical call.

CC2D2A p.Pro721Ser

c.2161C>T · rs199768782 · VCV194821

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9533 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.9533	likely pathogenic · top 4% in CC2D2A
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -10.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	26.3	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 1.01% South Asian · 843/83,752 alleles

Filtering AF 0.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.928%

Overall 0.16% 2,477/1,549,670 alleles · low-frequency exomes 2,308/1,397,454 · genomes 169/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.01%	99
Ashkenazi Jewishnot grpmax-eligible	0.794%	126
Middle Eastern	0.568%	176
Remaining individualsnot grpmax-eligible	0.22%	455
European (non-Finnish)	0.104%	960
Admixed American	0.061%	1,640
African / African-American	0.0205%	4,872
East Asian	0.00244%	40,904
Finnishnot grpmax-eligible	0.00167%	59,870

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.Pro721Ser
Coding: c.2161C>T
MANE Select: NM_001378615
dbSNP: rs199768782
Type: single nucleotide variant
Location: chr4:15540994 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 721: a UniProt-annotated variant site (in jbts9)

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 1 Meckel syndrome, type 6 Joubert syndrome

Similar variants

CC2D2A p.Pro721= Conflicting classifications of pathogenicity ★ same residue
CC2D2A p.Pro721Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A c.1017+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-pro721ser (accessed [today's date]).

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