CEP290 p.Leu489Pro
c.1466T>C · rs1340148485 · VCV2932624
ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
Uncertain Significance for CEP290-related ciliopathy. Applied ACMG criteria (verbatim):
PM2_Supporting PP1 PP3 PM3
Curation rationale (ClinGen, verbatim)
NM_025114.4(CEP290):c.1466T>C (p.Leu489Pro) is a missense variant that replaces leucine with proline at amino acid 489. This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.0000006505, with 1 allele / 1,537,272 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_025114.4(CEP290):c.1666del (p.Ile556fs) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PMID: 34196655, PM3). The proband exhibits a phenotype including diagnosis of either Leber congenital amaurosis, early onset severe retinal dystrophy, or retinitis pigmentosa (0.5 pts), which is not sufficiently specific for CEP290-related ciliopathy to meet the PP4 code (0.5 total points, PMID: 34196655). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 34196655, PP1). The computational predictor CADD gives a score of 26.5, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3, and PP1. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.964 | likely pathogenic · top 1% in CEP290 |
|---|---|---|
| REVEL | 0.503 | indeterminate |
| SaProt | LLR -14.32 | damaging |
| ⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.6, phastCons 1 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic |
| Overall | ||
| CADD | 27.1 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Leu489Pro
- Coding
- c.1466T>C
- MANE Select
- NM_025114
- dbSNP
- rs1340148485
- Type
- single nucleotide variant
- Location
- chr12:88120170 (GRCh38)
- Gene constraint
- LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 60.90
- Residue 489
- 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)
Similar variants
- CEP290 p.Leu489Ile Uncertain significance ★ ⚠ same residue
- 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.4438-2A>G Pathogenic ★★★ same condition
- CEP290 c.6271-8T>G Pathogenic ★★★ same condition
- CEP290 p.Arg1272Ter 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-leu489pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown