Is CEP290 p.Ile2000Thr (c.5999T>C) pathogenic?

CEP290 p.Ile2000Thr (c.5999T>C) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-22). AlphaMissense: ambiguous (0.4253); Ultra-rare (popmax 0.0112%, eas); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Ile2000Thr (c.5999T>C)?

CEP290 p.Ile2000Thr (c.5999T>C) is associated with Joubert syndrome, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Ile2000Thr (c.5999T>C) in the general population?

CEP290 p.Ile2000Thr (c.5999T>C) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about CEP290 p.Ile2000Thr (c.5999T>C)?

AlphaMissense predicts ambiguous (score 0.4253) — an in-silico prediction, not a clinical call.

CEP290 p.Ile2000Thr

c.5999T>C · rs1592782496 · VCV1043237

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.4253	ambiguous
REVEL	0.221	benign-leaning
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,732 alleles

Filtering AF 0.00436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.000344% 5/1,452,722 alleles · ultra-rare

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.Ile2000Thr
Coding: c.5999T>C
MANE Select: NM_025114
dbSNP: rs1592782496
Type: single nucleotide variant
Location: chr12:88071306 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 2000: 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); a UniProt-annotated variant site (in lca10 and slsn6); a UniProt-annotated variant site (in mks4 and jbts5); the 'self-association (with itself or n-terminus)' 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: Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Meckel syndrome Leber congenital amaurosis nephronophthisis

Similar variants

CEP290 p.Ile2000Val 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
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-ile2000thr (accessed [today's date]).

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