Is CEP290 p.Arg504fs (c.1512_1515del) pathogenic?

CEP290 p.Arg504fs (c.15121515del) is classified Pathogenic/Likely pathogenic in CEP290 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-01-08). Very rare (popmax 0.000176%, nfe); Associated with CEP290-related disorder.

What condition is associated with CEP290 p.Arg504fs (c.1512_1515del)?

CEP290 p.Arg504fs (c.1512_1515del) is associated with CEP290-related disorder, blindness (disorder), Joubert syndrome 5 (ClinVar).

How common is CEP290 p.Arg504fs (c.1512_1515del) in the general population?

CEP290 p.Arg504fs (c.1512_1515del) is very rare (popmax 0.000176%, nfe) (gnomAD).

CEP290 p.Arg504fs

c.1512_1515del · rs886043303 · VCV286074

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000176%, nfe)

Conditions

CEP290-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 54
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 2.6, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000176% European (non-Finnish) · 2/1,135,134 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000131% 2/1,526,362 alleles · very rare

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.Arg504fs
Coding: c.1512_1515del
MANE Select: NM_025114
dbSNP: rs886043303
Type: Microsatellite
Location: chr12:88120121 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 504: 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

Also linked: blindness (disorder)Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Arg504= Likely benign ★ same residue
CEP290 p.Glu1554del Pathogenic ★★★ same condition
CEP290 p.Glu1656fs Pathogenic ★★★ same condition
CEP290 p.Glu245fs Pathogenic ★★★ same condition
CEP290 p.Lys1484fs Pathogenic ★★★ same condition
CEP290 p.Met407fs Pathogenic ★★★ same condition
CEP290 p.Glu23del Uncertain significance ★★★ same condition
CEP290 c.2484-18GTTTT[4] Likely benign ★★★ 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-arg504fs (accessed [today's date]).

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