Is CC2D2A p.Phe308Leu (c.922T>C) pathogenic?

CC2D2A p.Phe308Leu (c.922T>C) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.9274); Rare (popmax 0.716%, sas); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Phe308Leu (c.922T>C)?

CC2D2A p.Phe308Leu (c.922T>C) is associated with Joubert syndrome, Meckel syndrome, type 6, Joubert syndrome 9 (ClinVar).

How common is CC2D2A p.Phe308Leu (c.922T>C) in the general population?

CC2D2A p.Phe308Leu (c.922T>C) is rare (popmax 0.716%, sas) (gnomAD).

What do computational predictors say about CC2D2A p.Phe308Leu (c.922T>C)?

AlphaMissense predicts likely pathogenic (score 0.9274) — an in-silico prediction, not a clinical call.

CC2D2A p.Phe308Leu

c.922T>C · rs201465430 · VCV506421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9274 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.716%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.9274	likely pathogenic · top 6% in CC2D2A
REVEL	0.103	moderately benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	23.9	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 0.716% South Asian · 603/84,206 alleles

Filtering AF 0.669% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.65%

Overall 0.0521% 811/1,555,626 alleles · rare exomes 768/1,403,364 · genomes 43/152,262 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.716%	140
Middle Eastern	0.367%	273
Remaining individualsnot grpmax-eligible	0.0696%	1,438
Admixed American	0.0254%	3,941
European (non-Finnish)	0.0111%	9,050
African / African-American	0.00409%	24,450
East Asian	0.00243%	41,174

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.Phe308Leu
Coding: c.922T>C
MANE Select: NM_001378615
dbSNP: rs201465430
Type: single nucleotide variant
Location: chr4:15515909 (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

Joubert syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Meckel syndrome, type 6 Joubert syndrome 9 Meckel 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-phe308leu (accessed [today's date]).

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