Is CEP290 p.Lys689= (c.2067G>A) pathogenic?

CEP290 p.Lys689= (c.2067G>A) is classified Likely benign in CEP290 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-07-20). Very rare (popmax 0.000513%, nfe); Associated with CEP290-related ciliopathy.

What condition is associated with CEP290 p.Lys689= (c.2067G>A)?

CEP290 p.Lys689= (c.2067G>A) is associated with CEP290-related ciliopathy, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CEP290 p.Lys689= (c.2067G>A) in the general population?

CEP290 p.Lys689= (c.2067G>A) is very rare (popmax 0.000513%, nfe) (gnomAD).

CEP290 p.Lys689=

c.2067G>A · rs1425613490 · VCV595539

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000513%, nfe)

Conditions

CEP290-related ciliopathy

ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Likely Benign for CEP290-related ciliopathy. Applied ACMG criteria (verbatim):

PM2_Supporting BP7 BP4

Curation rationale (ClinGen, verbatim)

NM_025114.4(CEP290):c.2067G>A (p.Lys689=) is a synonymous variant in exon 21 that does not have predicted impact on CEP290 splicing (BP7). The splicing impact predictor SpliceAI gives a delta score of 0.03 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.00000185 with 6 alleles / 1,592,018 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP7, BP4, and PM2_Supporting. (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
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.143	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -1.6, phastCons 0.93
Overall
CADD	9.527	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000513% European (non-Finnish) · 6/1,169,674 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000417% 6/1,439,862 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.Lys689=
Coding: c.2067G>A
MANE Select: NM_025114
dbSNP: rs1425613490
Type: single nucleotide variant
Location: chr12:88111844 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 689: 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: Joubert syndrome Meckel 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.4438-2A>G Pathogenic ★★★ same condition
CEP290 c.6271-8T>G Pathogenic ★★★ same condition
CEP290 p.Arg1272Ter Pathogenic ★★★ same condition
CEP290 p.Arg1465Ter 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-lys689 (accessed [today's date]).

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