Is CEP290 p.Arg816Pro (c.2447G>C) pathogenic?

CEP290 p.Arg816Pro (c.2447G>C) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.984); Very rare (popmax 0.00295%, afr); Associated with Inborn genetic diseases.

What condition is associated with CEP290 p.Arg816Pro (c.2447G>C)?

CEP290 p.Arg816Pro (c.2447G>C) is associated with Inborn genetic diseases, Joubert syndrome, Meckel syndrome (ClinVar).

How common is CEP290 p.Arg816Pro (c.2447G>C) in the general population?

CEP290 p.Arg816Pro (c.2447G>C) is very rare (popmax 0.00295%, afr) (gnomAD).

What do computational predictors say about CEP290 p.Arg816Pro (c.2447G>C)?

AlphaMissense predicts likely pathogenic (score 0.984) — an in-silico prediction, not a clinical call.

CEP290 p.Arg816Pro

c.2447G>C · rs768448895 · VCV1378930

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00295%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.984	likely pathogenic · top 1% in CEP290
REVEL	0.171	moderately benign-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	28.9	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 0.00295% African / African-American · 2/67,862 alleles

Filtering AF 0.000489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000183%

Overall 0.000207% 3/1,446,210 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00295%	33,931
European (non-Finnish)	9.27e-05%	1,078,734

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.Arg816Pro
Coding: c.2447G>C
MANE Select: NM_025114
dbSNP: rs768448895
Type: single nucleotide variant
Location: chr12:88109102 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 816: a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); the 'interaction with iqcb1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Arg816Cys Uncertain significance ★★ ⚠ same residue
CEP290 p.Arg816His Uncertain significance ★★ ⚠ same residue
CEP290 p.Arg816= Likely benign ★★ same residue
CEP290 p.Arg816Leu 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

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-arg816pro (accessed [today's date]).

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