Is CEP290 p.Ser753= (c.2259A>G) pathogenic?

CEP290 p.Ser753= (c.2259A>G) is classified Likely benign in CEP290 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-07). Very rare (popmax 0.00136%, afr); Associated with Meckel syndrome.

What condition is associated with CEP290 p.Ser753= (c.2259A>G)?

CEP290 p.Ser753= (c.2259A>G) is associated with Meckel syndrome, Joubert syndrome, nephronophthisis (ClinVar).

How common is CEP290 p.Ser753= (c.2259A>G) in the general population?

CEP290 p.Ser753= (c.2259A>G) is very rare (popmax 0.00136%, afr) (gnomAD).

CEP290 p.Ser753=

c.2259A>G · rs1269755462 · VCV2194086

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

Meckel syndrome

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 0.65	GERP 0.28, phastCons 0.31
Overall
CADD	12.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,472 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000438%

Overall 0.000896% 14/1,563,222 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,472
South Asian	0.0012%	83,454
European (non-Finnish)	0.00104%	96,172

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.Ser753=
Coding: c.2259A>G
MANE Select: NM_025114
dbSNP: rs1269755462
Type: single nucleotide variant
Location: chr12:88111310 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 753: a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); the 'interaction with iqcb1' region

Full CEP290 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meckel syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome nephronophthisis

Similar variants

CEP290 p.Ser753Ter Pathogenic/Likely pathogenic ★★ 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
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-ser753 (accessed [today's date]).

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