Is CEP290 p.Ile1059Val (c.3175A>G) pathogenic?

CEP290 p.Ile1059Val (c.3175A>G) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-20). AlphaMissense: likely benign (0.1781); Very rare (popmax 0.00842%, amr); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Ile1059Val (c.3175A>G)?

CEP290 p.Ile1059Val (c.3175A>G) is associated with Joubert syndrome, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Ile1059Val (c.3175A>G) in the general population?

CEP290 p.Ile1059Val (c.3175A>G) is very rare (popmax 0.00842%, amr) (gnomAD).

What do computational predictors say about CEP290 p.Ile1059Val (c.3175A>G)?

AlphaMissense predicts likely benign (score 0.1781) — an in-silico prediction, not a clinical call.

CEP290 p.Ile1059Val

c.3175A>G · rs771815959 · VCV1408014

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00842%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1781	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.45	acceptor gain · deltas
Pangolin	Δ0.41	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	29.6	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 0.00842% Admixed American · 5/59,362 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.00075% 12/1,600,682 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00842%	11,872
European (non-Finnish)	0.000598%	167,255

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.Ile1059Val
Coding: c.3175A>G
MANE Select: NM_025114
dbSNP: rs771815959
Type: single nucleotide variant
Location: chr12:88093904 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1059: a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); a UniProt-annotated variant site (in lca10)

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: Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Ile1059Lys Uncertain significance ★★ ⚠ same residue
CEP290 p.Ile1059Leu Uncertain significance ★ ⚠ same residue
CEP290 p.Ile1059fs 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

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-ile1059val (accessed [today's date]).

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