Is CEP290 p.Leu577= (c.1729C>T) pathogenic?

CEP290 p.Leu577= (c.1729C>T) is classified Conflicting classifications of pathogenicity in CEP290 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-25). Rare (popmax 0.438%, mid); Associated with Leber congenital amaurosis 10.

What condition is associated with CEP290 p.Leu577= (c.1729C>T)?

CEP290 p.Leu577= (c.1729C>T) is associated with Leber congenital amaurosis 10, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Leu577= (c.1729C>T) in the general population?

CEP290 p.Leu577= (c.1729C>T) is rare (popmax 0.438%, mid) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CEP290 p.Leu577=

c.1729C>T · rs201295052 · VCV388113

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.438%, mid)

Conditions

Leber congenital amaurosis 10

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 0.26	GERP -0.68, phastCons 0.61
Overall
CADD	1.286	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.438% Middle Eastern · 26/5,936 alleles

Filtering AF 0.307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.263%

Overall 0.0186% 286/1,535,606 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.438%	228
Ashkenazi Jewishnot grpmax-eligible	0.36%	278
Remaining individualsnot grpmax-eligible	0.0419%	2,385
Admixed American	0.0174%	5,755
European (non-Finnish)	0.00993%	10,075
South Asian	0.00834%	11,984
African / African-American	0.00548%	18,250

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.Leu577=
Coding: c.1729C>T
MANE Select: NM_025114
dbSNP: rs201295052
Type: single nucleotide variant
Location: chr12:88117128 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 577: 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

Leber congenital amaurosis 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome nephronophthisis

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

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-leu577 (accessed [today's date]).

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