Is CEP290 p.Glu480= (c.1440A>G) pathogenic?

CEP290 p.Glu480= (c.1440A>G) is classified Conflicting classifications of pathogenicity in CEP290 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-01). Very rare (popmax 0.00557%, nfe); Associated with Meckel syndrome.

What condition is associated with CEP290 p.Glu480= (c.1440A>G)?

CEP290 p.Glu480= (c.1440A>G) is associated with Meckel syndrome, Joubert syndrome, nephronophthisis (ClinVar).

How common is CEP290 p.Glu480= (c.1440A>G) in the general population?

CEP290 p.Glu480= (c.1440A>G) is very rare (popmax 0.00557%, nfe) (gnomAD).

CEP290 p.Glu480=

c.1440A>G · rs777299440 · VCV210692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00557%, nfe)

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 4.1	GERP 1.3, phastCons 1
Overall
CADD	10.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00557% European (non-Finnish) · 63/1,130,696 alleles

Filtering AF 0.00445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00434% 66/1,520,550 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00557%	17,948
Remaining individualsnot grpmax-eligible	0.0051%	19,626

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: CEP290
Protein: p.Glu480=
Coding: c.1440A>G
MANE Select: NM_025114
dbSNP: rs777299440
Type: single nucleotide variant
Location: chr12:88120196 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 480: the 'self-association (with itself or c-terminus)' region; a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss)

Full CEP290 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 nephronophthisis

Similar variants

CEP290 c.1189+1G>A Pathogenic ★★★ same condition
CEP290 c.1189+2T>C Pathogenic ★★★ same condition
CEP290 c.297+1G>T Pathogenic ★★★ same condition
CEP290 c.2991+1655A>G Pathogenic ★★★ same condition
CEP290 c.6271-8T>G Pathogenic ★★★ same condition
CEP290 p.Arg1272Ter Pathogenic ★★★ same condition
CEP290 p.Arg1465Ter Pathogenic ★★★ same condition
CEP290 p.Arg1752Trp 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/cep290-p-glu480 (accessed [today's date]).

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