Is CEP290 p.Ala774Pro (c.2320G>C) pathogenic?

CEP290 p.Ala774Pro (c.2320G>C) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-05). AlphaMissense: ambiguous (0.3897); Ultra-rare (popmax 0.018%, mid); Associated with CEP290-related disorder.

What condition is associated with CEP290 p.Ala774Pro (c.2320G>C)?

CEP290 p.Ala774Pro (c.2320G>C) is associated with CEP290-related disorder, intellectual disability, Joubert syndrome (ClinVar).

How common is CEP290 p.Ala774Pro (c.2320G>C) in the general population?

CEP290 p.Ala774Pro (c.2320G>C) is ultra-rare (popmax 0.018%, mid) (gnomAD).

What do computational predictors say about CEP290 p.Ala774Pro (c.2320G>C)?

AlphaMissense predicts ambiguous (score 0.3897) — an in-silico prediction, not a clinical call.

CEP290 p.Ala774Pro

c.2320G>C · rs777365811 · VCV975662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3897 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CEP290-related disorder

Computational evidence

Protein change
AlphaMissense	0.3897	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	25.9	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 0.018% Middle Eastern · 1/5,548 alleles

Filtering AF 0.000843% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000682%

Overall 0.0012% 18/1,500,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.018%	5,548
Remaining individualsnot grpmax-eligible	0.00173%	57,786
European (non-Finnish)	0.00142%	70,234

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.Ala774Pro
Coding: c.2320G>C
MANE Select: NM_025114
dbSNP: rs777365811
Type: single nucleotide variant
Location: chr12:88111249 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 774: 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

Also linked: intellectual disability Joubert syndrome Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Ala774Gly Uncertain significance ★ ⚠ same residue
CEP290 p.Ala774= Likely benign ★ 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-ala774pro (accessed [today's date]).

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