Is CC2D2A p.Thr1517Ser (c.4550C>G) pathogenic?

CC2D2A p.Thr1517Ser (c.4550C>G) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.8021); Very rare (popmax 0.00162%, nfe); Associated with CC2D2A-related disorder.

What condition is associated with CC2D2A p.Thr1517Ser (c.4550C>G)?

CC2D2A p.Thr1517Ser (c.4550C>G) is associated with CC2D2A-related disorder, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CC2D2A p.Thr1517Ser (c.4550C>G) in the general population?

CC2D2A p.Thr1517Ser (c.4550C>G) is very rare (popmax 0.00162%, nfe) (gnomAD).

What do computational predictors say about CC2D2A p.Thr1517Ser (c.4550C>G)?

AlphaMissense predicts likely pathogenic (score 0.8021) — an in-silico prediction, not a clinical call.

CC2D2A p.Thr1517Ser

c.4550C>G · rs780673487 · VCV372317

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00162%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CC2D2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.8021	likely pathogenic
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -10.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.69 · regional, not allelic
Overall
CADD	25.3	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 0.00162% European (non-Finnish) · 19/1,175,874 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00118% 19/1,607,982 alleles · very rare exomes 17/1,455,810 · genomes 2/152,172 · joint denominator

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.Thr1517Ser
Coding: c.4550C>G
MANE Select: NM_001378615
dbSNP: rs780673487
Type: single nucleotide variant
Location: chr4:15599582 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 69.46
Residue 1517: a UniProt-annotated variant site (in mks6; uncertain significance)

Full CC2D2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Joubert syndrome Meckel syndrome

Similar variants

CC2D2A p.Thr1517Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CC2D2A p.Thr1517= Likely benign ★ 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-thr1517ser (accessed [today's date]).

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