Is CEP290 p.Arg557Cys (c.1669C>T) pathogenic?

CEP290 p.Arg557Cys (c.1669C>T) is classified Conflicting classifications of pathogenicity in CEP290 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-12-18). AlphaMissense: ambiguous (0.4005); Ultra-rare (popmax 0.0391%, eas); Associated with Bardet-Biedl syndrome 14.

What condition is associated with CEP290 p.Arg557Cys (c.1669C>T)?

CEP290 p.Arg557Cys (c.1669C>T) is associated with Bardet-Biedl syndrome 14, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Arg557Cys (c.1669C>T) in the general population?

CEP290 p.Arg557Cys (c.1669C>T) is ultra-rare (popmax 0.0391%, eas) (gnomAD).

How is Bardet-Biedl syndrome inherited?

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

What do computational predictors say about CEP290 p.Arg557Cys (c.1669C>T)?

AlphaMissense predicts ambiguous (score 0.4005) — an in-silico prediction, not a clinical call.

CEP290 p.Arg557Cys

c.1669C>T · rs561018129 · VCV261828

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0391%, eas)

Conditions

Bardet-Biedl syndrome 14

Computational evidence

Protein change
AlphaMissense	0.4005	ambiguous
REVEL	0.382	indeterminate
SaProt	LLR -9.21	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	33.0	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 0.0391% East Asian · 17/43,474 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.00667% 105/1,574,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0391%	2,557
Ashkenazi Jewishnot grpmax-eligible	0.0104%	9,659
Remaining individualsnot grpmax-eligible	0.00819%	12,211
European (non-Finnish)	0.00665%	15,037
South Asian	0.0023%	43,394
African / African-American	0.00135%	74,130

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.Arg557Cys
Coding: c.1669C>T
MANE Select: NM_025114
dbSNP: rs561018129
Type: single nucleotide variant
Location: chr12:88118525 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 557: 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

Bardet-Biedl syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Joubert syndrome Meckel syndrome nephronophthisis

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

CEP290 p.Arg557His Conflicting classifications of pathogenicity ★ ⚠ same residue
CEP290 p.Arg557fs Pathogenic/Likely pathogenic ★★ same residue
CEP290 p.Arg557Gly 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.6271-8T>G 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-arg557cys (accessed [today's date]).

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