Is CEP290 p.Ser756= (c.2268A>G) pathogenic?

CEP290 p.Ser756= (c.2268A>G) is classified Benign in CEP290 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 95.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with CEP290 p.Ser756= (c.2268A>G)?

CEP290 p.Ser756= (c.2268A>G) is associated with inherited retinal dystrophy, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

CEP290 p.Ser756=

Q: How common is CEP290 p.Ser756= (c.2268A>G) in the general population?

CEP290 p.Ser756= (c.2268A>G) is common (popmax 95.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2268A>G · rs2468255 · VCV126249

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 95.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

inherited retinal dystrophy

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 -0.24	GERP -3.4, phastCons 0.31
Overall
CADD	10.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 95.5% East Asian · 40,397/42,290 alleles

Filtering AF 94.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 94.4%

Overall 90% 1,402,528/1,558,632 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	96.1%	1
East Asiangrpmax	95.5%	1
European (non-Finnish)	92.7%	1
Amishnot grpmax-eligible	92.3%	1
Ashkenazi Jewishnot grpmax-eligible	90.2%	1
Admixed American	90.1%	1
Middle Eastern	89.8%	1
South Asian	89.2%	1
Remaining individualsnot grpmax-eligible	88.7%	1
African / African-American	40.2%	2

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser756=
Coding: c.2268A>G
MANE Select: NM_025114
dbSNP: rs2468255
Type: single nucleotide variant
Location: chr12:88111301 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 756: 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

inherited retinal dystrophy — 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 Leber congenital amaurosis nephronophthisis

Similar variants

CEP290 p.Ser756Ter Likely pathogenic ★ same residue
CEP290 p.Ser756Leu 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
CEP290 p.Arg1272Ter 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-ser756 (accessed [today's date]).

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