Is CC2D2A p.Val533Ala (c.1598T>C) pathogenic?

CC2D2A p.Val533Ala (c.1598T>C) is classified Conflicting classifications of pathogenicity in CC2D2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.2555); Ultra-rare (popmax 0.0582%, sas); Associated with Meckel syndrome.

What condition is associated with CC2D2A p.Val533Ala (c.1598T>C)?

CC2D2A p.Val533Ala (c.1598T>C) is associated with Meckel syndrome, Joubert syndrome (ClinVar).

How common is CC2D2A p.Val533Ala (c.1598T>C) in the general population?

CC2D2A p.Val533Ala (c.1598T>C) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about CC2D2A p.Val533Ala (c.1598T>C)?

AlphaMissense predicts likely benign (score 0.2555) — an in-silico prediction, not a clinical call.

CC2D2A p.Val533Ala

c.1598T>C · rs777351655 · VCV283903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meckel syndrome

Computational evidence

Protein change
AlphaMissense	0.2555	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 104 kb · p 0.09 · regional, not allelic
Overall
CADD	23.1	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 0.0582% South Asian · 47/80,754 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0402%

Overall 0.00399% 62/1,552,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,718
Remaining individualsnot grpmax-eligible	0.00166%	60,220
European (non-Finnish)	0.00122%	82,246

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.Val533Ala
Coding: c.1598T>C
MANE Select: NM_001378615
dbSNP: rs777351655
Type: single nucleotide variant
Location: chr4:15533324 (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

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

Also linked: Joubert syndrome

Similar variants

CC2D2A p.Val533fs Pathogenic ★ 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>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

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-val533ala (accessed [today's date]).

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