Is CEP290 p.Asp1499Val (c.4496A>T) pathogenic?

CEP290 p.Asp1499Val (c.4496A>T) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.8114); Absent from gnomAD v4.1; Associated with Joubert syndrome.

What condition is associated with CEP290 p.Asp1499Val (c.4496A>T)?

CEP290 p.Asp1499Val (c.4496A>T) is associated with Joubert syndrome, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Asp1499Val (c.4496A>T) in the general population?

CEP290 p.Asp1499Val (c.4496A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CEP290 p.Asp1499Val (c.4496A>T)?

AlphaMissense predicts likely pathogenic (score 0.8114) — an in-silico prediction, not a clinical call.

CEP290 p.Asp1499Val

c.4496A>T · rs2036455482 · VCV1009556

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8114 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.8114	likely pathogenic · top 5% in CEP290
REVEL	0.526	indeterminate
SaProt	LLR -10.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CEP290
Protein: p.Asp1499Val
Coding: c.4496A>T
MANE Select: NM_025114
dbSNP: rs2036455482
Type: single nucleotide variant
Location: chr12:88084794 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1499: 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); a UniProt-annotated variant site (in lca10, slsn6 and mks4)

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 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
CEP290 p.Arg1752Trp Likely 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-asp1499val (accessed [today's date]).

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