Is CC2D2A p.Pro320Ser (c.958C>T) pathogenic?

CC2D2A p.Pro320Ser (c.958C>T) is classified Uncertain significance in CC2D2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-13). AlphaMissense: ambiguous (0.4572); Very rare (popmax 0.00117%, sas); Associated with Joubert syndrome.

What condition is associated with CC2D2A p.Pro320Ser (c.958C>T)?

CC2D2A p.Pro320Ser (c.958C>T) is associated with Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Pro320Ser (c.958C>T) in the general population?

CC2D2A p.Pro320Ser (c.958C>T) is very rare (popmax 0.00117%, sas) (gnomAD).

What do computational predictors say about CC2D2A p.Pro320Ser (c.958C>T)?

AlphaMissense predicts ambiguous (score 0.4572) — an in-silico prediction, not a clinical call.

CC2D2A p.Pro320Ser

c.958C>T · rs374098727 · VCV1025148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00117%, sas)

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.4572	ambiguous
REVEL	0.334	indeterminate
SaProt	LLR -7.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	24.3	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 0.00117% South Asian · 1/85,318 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000265%

Overall 0.000635% 10/1,573,618 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00117%	85,318
European (non-Finnish)	0.000776%	128,799

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.Pro320Ser
Coding: c.958C>T
MANE Select: NM_001378615
dbSNP: rs374098727
Type: single nucleotide variant
Location: chr4:15515945 (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

Similar variants

CC2D2A c.1017+1G>A Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.123+2T>G 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
CC2D2A c.2004-17A>G Pathogenic/Likely pathogenic ★★ same condition
CC2D2A c.2486+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-pro320ser (accessed [today's date]).

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