Is CEP290 p.Phe520Leu (c.1558T>C) pathogenic?

CEP290 p.Phe520Leu (c.1558T>C) is classified Benign in CEP290 (ClinVar, Expert panel, 10 submitters; last evaluated 2026-07-20). AlphaMissense: likely pathogenic (0.7378); Low-frequency (popmax 1.85%, afr); Associated with CEP290-related ciliopathy.

What condition is associated with CEP290 p.Phe520Leu (c.1558T>C)?

CEP290 p.Phe520Leu (c.1558T>C) is associated with CEP290-related ciliopathy, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Phe520Leu (c.1558T>C) in the general population?

CEP290 p.Phe520Leu (c.1558T>C) is low-frequency (popmax 1.85%, afr) (gnomAD).

What do computational predictors say about CEP290 p.Phe520Leu (c.1558T>C)?

AlphaMissense predicts likely pathogenic (score 0.7378) — an in-silico prediction, not a clinical call.

CEP290 p.Phe520Leu

c.1558T>C · rs147371999 · VCV261827

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.7378 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.85%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CEP290-related ciliopathy

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

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

BS2 BA1

Curation rationale (ClinGen, verbatim)

NM_025114.4(CEP290):c.1558T>C (p.Phe520Leu) is a missense variant that replaces phenylalanine with leucine at amino acid 520. This variant is present in gnomAD v4.1.1 at a Grpmax allele frequency of 0.01772, with 1,655 alleles / 1,612,938 total alleles in the African/African-American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 30 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.1; BS2). The computational predictor CADD gives a PHRED score of 22.5, which is above the ClinGen LCA/eoRD VCEP threshold of <17.3 and does not predict a non-damaging effect on CEP290 protein function, so BP4 is not met. The splicing impact predictor SpliceAI gives a delta score of 0.09 for donor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing. In summary, this variant meets the criteria to be classified as Benign for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1 and BS2. (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	0.7378	likely pathogenic · top 7% in CEP290
REVEL	0.215	benign-leaning
SaProt	LLR -4.03	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	22.2	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 1.85% African / African-American · 1,390/75,010 alleles

Filtering AF 1.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.74%

Overall 0.103% 1,655/1,612,938 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.85%	54
Admixed American	0.167%	600
Remaining individualsnot grpmax-eligible	0.128%	781
Middle Eastern	0.0496%	2,018
European (non-Finnish)	0.00695%	14,385

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.Phe520Leu
Coding: c.1558T>C
MANE Select: NM_025114
dbSNP: rs147371999
Type: single nucleotide variant
Location: chr12:88118708 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 520: 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 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome nephronophthisis

Similar variants

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CEP290 c.2991+1655A>G Pathogenic ★★★ same condition
CEP290 c.4438-2A>G Pathogenic ★★★ same condition
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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-phe520leu (accessed [today's date]).

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