Is CEP290 p.Pro1448Arg (c.4343C>G) pathogenic?

CEP290 p.Pro1448Arg (c.4343C>G) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-19). AlphaMissense: ambiguous (0.345); Very rare (popmax 0.00381%, nfe); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Pro1448Arg (c.4343C>G)?

CEP290 p.Pro1448Arg (c.4343C>G) is associated with Joubert syndrome, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Pro1448Arg (c.4343C>G) in the general population?

CEP290 p.Pro1448Arg (c.4343C>G) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about CEP290 p.Pro1448Arg (c.4343C>G)?

AlphaMissense predicts ambiguous (score 0.345) — an in-silico prediction, not a clinical call.

CEP290 p.Pro1448Arg

c.4343C>G · rs757356455 · VCV1020611

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.345 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.345	ambiguous
REVEL	0.402	indeterminate
SaProt	LLR -8.53	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	27.1	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 0.00381% European (non-Finnish) · 45/1,179,564 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00291% 47/1,612,770 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,213
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Finnishnot grpmax-eligible	0.00156%	63,966

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.Pro1448Arg
Coding: c.4343C>G
MANE Select: NM_025114
dbSNP: rs757356455
Type: single nucleotide variant
Location: chr12:88086133 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1448: 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 Leber congenital amaurosis nephronophthisis

Similar variants

CEP290 p.Pro1448= Likely benign ★ same residue
CEP290 p.Pro1448Leu 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

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-pro1448arg (accessed [today's date]).

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