Is CEP290 p.Leu343Pro (c.1028T>C) pathogenic?

CEP290 p.Leu343Pro (c.1028T>C) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.7009); Very rare (popmax 0.00106%, nfe); Associated with Joubert syndrome 5.

What condition is associated with CEP290 p.Leu343Pro (c.1028T>C)?

CEP290 p.Leu343Pro (c.1028T>C) is associated with Joubert syndrome 5, Senior-Loken syndrome 6, Meckel syndrome, type 4 (ClinVar).

How common is CEP290 p.Leu343Pro (c.1028T>C) in the general population?

CEP290 p.Leu343Pro (c.1028T>C) is very rare (popmax 0.00106%, nfe) (gnomAD).

What do computational predictors say about CEP290 p.Leu343Pro (c.1028T>C)?

AlphaMissense predicts likely pathogenic (score 0.7009) — an in-silico prediction, not a clinical call.

CEP290 p.Leu343Pro

c.1028T>C · rs1429640081 · VCV971538

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7009 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00106%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome 5

Computational evidence

Protein change
AlphaMissense	0.7009	likely pathogenic · top 8% in CEP290
REVEL	0.461	indeterminate
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	27.0	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 0.00106% European (non-Finnish) · 12/1,129,956 alleles

Filtering AF 0.000566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000447%

Overall 0.000889% 12/1,349,692 alleles · very 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.Leu343Pro
Coding: c.1028T>C
MANE Select: NM_025114
dbSNP: rs1429640081
Type: single nucleotide variant
Location: chr12:88126353 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 343: the 'self-association (with itself or c-terminus)' region; a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss)

Full CEP290 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome Leber congenital amaurosis 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-leu343pro (accessed [today's date]).

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