Is CEP290 p.Ile856Val (c.2566A>G) pathogenic?

CEP290 p.Ile856Val (c.2566A>G) is classified Uncertain significance in CEP290 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely benign (0.0567); Very rare (popmax 0.00274%, afr); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Ile856Val (c.2566A>G)?

CEP290 p.Ile856Val (c.2566A>G) is associated with Joubert syndrome, Meckel syndrome, nephronophthisis (ClinVar).

How common is CEP290 p.Ile856Val (c.2566A>G) in the general population?

CEP290 p.Ile856Val (c.2566A>G) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about CEP290 p.Ile856Val (c.2566A>G)?

AlphaMissense predicts likely benign (score 0.0567) — an in-silico prediction, not a clinical call.

CEP290 p.Ile856Val

c.2566A>G · rs1003364525 · VCV2159239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.0567	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.70	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 0.56	GERP 0.44, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	5.557	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00274% African / African-American · 2/72,886 alleles

Filtering AF 0.000455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000215% 3/1,398,072 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,443
Remaining individualsnot grpmax-eligible	0.00166%	60,100

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.Ile856Val
Coding: c.2566A>G
MANE Select: NM_025114
dbSNP: rs1003364525
Type: single nucleotide variant
Location: chr12:88107016 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 856: 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

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

Also linked: Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Ile856= Likely benign ★★ 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-ile856val (accessed [today's date]).

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