Is CC2D2A p.Val1111= (c.3333T>C) pathogenic?

CC2D2A p.Val1111= (c.3333T>C) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-11). Ultra-rare (popmax 0.0812%, sas); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Val1111= (c.3333T>C)?

CC2D2A p.Val1111= (c.3333T>C) is associated with Meckel syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Val1111= (c.3333T>C) in the general population?

CC2D2A p.Val1111= (c.3333T>C) is ultra-rare (popmax 0.0812%, sas) (gnomAD).

CC2D2A p.Val1111=

c.3333T>C · rs753770061 · VCV238277

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0812%, sas)

Conditions

Meckel syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -5.1
Overall
CADD	2.128	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0812% South Asian · 72/88,662 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0605%

Overall 0.00455% 73/1,605,748 alleles · ultra-rare exomes 65/1,453,416 · genomes 8/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0812%	1,231
Remaining individualsnot grpmax-eligible	0.00161%	62,154

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.Val1111=
Coding: c.3333T>C
MANE Select: NM_001378615
dbSNP: rs753770061
Type: single nucleotide variant
Location: chr4:15567721 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 1111: the c2 domain

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 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
CC2D2A c.1608-2A>G 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-val1111 (accessed [today's date]).

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