Is CEP290 p.Ile583Val (c.1747A>G) pathogenic?

CEP290 p.Ile583Val (c.1747A>G) is classified Conflicting classifications of pathogenicity in CEP290 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.0661); Very rare (popmax 0.00271%, afr); Associated with Senior-Loken syndrome 6.

What condition is associated with CEP290 p.Ile583Val (c.1747A>G)?

CEP290 p.Ile583Val (c.1747A>G) is associated with Senior-Loken syndrome 6, Joubert syndrome 5, Meckel syndrome, type 4 (ClinVar).

How common is CEP290 p.Ile583Val (c.1747A>G) in the general population?

CEP290 p.Ile583Val (c.1747A>G) is very rare (popmax 0.00271%, afr) (gnomAD).

How is Senior-Loken syndrome inherited?

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

What do computational predictors say about CEP290 p.Ile583Val (c.1747A>G)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

CEP290 p.Ile583Val

c.1747A>G · rs1459958084 · VCV991352

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Senior-Loken syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -4.3, phastCons 0.57
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	0.706	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% African / African-American · 2/73,782 alleles

Filtering AF 0.00045% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.000192% 3/1,561,002 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00271%	36,891
European (non-Finnish)	8.7e-05%	1,149,556

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.Ile583Val
Coding: c.1747A>G
MANE Select: NM_025114
dbSNP: rs1459958084
Type: single nucleotide variant
Location: chr12:88117110 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 583: 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

Senior-Loken syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 5 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Leber congenital amaurosis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

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-ile583val (accessed [today's date]).

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